GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE. METHODS: C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus. RESULTS: CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities. CONCLUSIONS: Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice.

Transient Receptor Potential Channels in Sensory Mechanisms of the Lower Urinary Tract.

BACKGROUND: Urine storage and excretion require a network of interactions in the urinary tract and the central nervous system, which is mediated by a reservoir of water in the bladder and the outlet to the bladder neck, urethra, and external urethral sphincter. Through communicating and coordinating each other, micturition system eventually showed a switch-like activity pattern. SUMMARY: At cervicothoracic and lumbosacral spine, the spinal reflex pathway of the lower urinary tract (LUT) received mechanosensory input from the urothelium to regulate the bladder contraction activity, thereby controlled urination voluntarily. Impairment of above-mentioned any level could result in lower urinary tract dysfunction, placed a huge burden on patients and society. Specific expression of purinergic receptors and transient receptor potential (TRP) channels are thought to play an important role in urinary excretion in the LUT. KEY MESSAGES: This article reviewed the knowledge about the voiding reflex and described the role and function of TRP channels during voiding.

Impact of radiation source activity on short- and long-term outcomes of cervical carcinoma patients treated with high-dose-rate brachytherapy: A retrospective cohort study.

OBJECTIVE: High-dose-rate (HDR) afterloading brachytherapy using Iridium-192 source involves large radiation activity varieties due to fast decay. It was unknown but clinically desirable to evaluate its impacts on patient outcomes to support more informed decisions. METHODS: Data of 510 cervical carcinoma (CC) patients were retrospectively included. High-radioactive (HR) and low-radioactive (LR) groups were statistically defined per patient-specific average mean-dose-rate (MDR) of all fractions. The cutoffs were calculated using R-3.6.1 packages based on significance of correlation with binary outcome or survival time. Categorized 1-month and 3-month follow-up results were analyzed as short-term outcomes. Long-term outcomes were evaluated using local recurrence-free survival (LRFS) and metastatic recurrence-free survival (MRFS). Propensity-score-matched (PSM) pairs were generated to reduce bias. RESULTS: The median follow-up time was 47.1 months (interquartile range: 33.9 months-66.4 months), involving MDR varieties of up to 9 folds ranging from 6059.99 cGy/h to 54013.66 cGy/h due to 17 source replacements at intervals ranging from 93 days-199 days. Both short-term (1-month: p = 0.22; 3-month: p = 0.79) and long-term (LRFS: p = 0.10; MRFS: p = 0.46) outcomes showed no significant difference between HR and LR. Subgroup analysis displayed significantly better results in LR for stage I-II (3-month, p = 0.02) and stage II (LRFS, p = 0.04) patients. Both LRFS and MRFS of LR were significantly non-inferior to HR (p ≤ 0.02). CONCLUSIONS: LR is clinically non-inferior or partially superior to HR for CC treatment using HDR, which dispels concerns of potentially undermined patient outcomes when source replacement is delayed.

Exponential subtraction in 3D ultrashort echo time imaging to visualize short T2 tissues in tibia.

BACKGROUND: Short T2 tissues can be directly visualized by dual-echo ultrashort echo time imaging with weighted subtraction. As a type of post-processing method, exponential subtraction of ultrashort echo time images with an optimal exponential factor is expected to provide improved positive short T2 contrast. PURPOSE: To test the feasibility and effectiveness of exponential subtraction in three-dimensional ultrashort echo time imaging and to determine the optimal exponential factor. MATERIAL AND METHODS: A dual-echo three-dimensional ultrashort echo time sequence was implemented on a 3-T MRI system. Exponential subtraction was performed on dual three-dimensional ultrashort echo time images of the tibia of seven healthy volunteers with exponential factors in the range of 1.00-3.00 in increments of 0.01. The regions of interest, including cortical bone, marrow, and muscle, were depicted on subtracted images of different exponential factors. Contrast-to-noise ratio values were calculated from these regions of interest and then used to assess the optimal exponential factor. To determine intra-observer agreement regarding region of interest selection, paired intra-observer measurements of regions of interest in all direct subtraction images were conducted with a one-week interval and the paired measurements were assessed using Bland-Altman analysis and paired-samples t-test. RESULTS: Cortical bone can be better visualized by using exponential subtraction in three-dimensional ultrashort echo time imaging; the suggested optimal exponential factor is 1.99-2.03 in the tibia. Paired measurements showed excellent intra-observer agreement. CONCLUSION: It is feasible to visualize cortical bone of the tibia using exponential subtraction in three-dimensional ultrashort echo time imaging. Compared with weighted subtraction images, exponential subtraction images with an optimal exponential factor provide enhanced visualization of short T2 tissues.

Radiological tissue equivalence of deformable silicone-based chemical radiation dosimeters (FlexyDos3D).

FlexyDos3D, a silicone-based chemical radiation dosimeter, has great potential to serve as a three-dimensional (3D) deformable dosimetric tool to verify complex dose distributions delivered by modern radiotherapy techniques. To facilitate its clinical application, its radiological tissue needs to be clarified. In this study we investigated its tissue-equivalence in comparison with water and Solid Water (RMI457). We found that its effective and mean atomic numbers were 40% and 20% higher and the total interaction probabilities for kV x-ray photons were larger than those of water respectively. To assess the influence of its over-response to kV photons, its HU value was measured by kV computed tomography (CT) and was found higher than all the soft-tissue substitutes. When applied for dose calculation without correction, this effect led to an 8% overestimation in electron density via HU-value mapping and 0.65% underestimation in target dose. Furthermore, depth dose curves (PDDs) and off-axis ratios (profiles) at various beam conditions as well as the dose distribution of a full-arc VMAT plan in FlexyDos3D and reference materials were simulated by Monte Carlo, where the results showed great agreement. As indicated, FlexyDos3D exhibits excellent radiological water-equivalence for clinical MV x-ray dosimetry, while its nonwater-equivalent effect for low energy x-ray dosimetry requires necessary correction. The key findings of this study provide pertinent reference for further FlexyDos3D characterization research.

Pediatric cone beam CT on Varian Halcyon and TrueBeam radiotherapy systems: radiation dose and positioning accuracy evaluations.

Medical exposure to ionizing irradiation has become a recognised carcinogenic risk. Balancing the concomitant imaging dose and positioning accuracy is critical in image-guided-radiotherapy (IGRT) especially for children, whose higher biological susceptibility and longer expected life make them more vulnerable to develop secondary cancer. This work aims to evaluate and benchmark the imaging dose and positioning accuracy of a new MV cone-beam-CT (CBCT)-guided IGRT system, Varian Halcyon, against conventional kV CBCT. Weighted-CT-dose-index (CTDIw) were measured for Varian TrueBeam kV CBCT, and computed for Halcyon MV CBCT using Eclipse system as validated before. Simulating the IGRT workflow, the positioning accuracy of correcting a known shift was tested on various regions of 1-year, 5-year and adult anthropomorphic phantoms, respectively. Inter-scanner and inter-protocol comparisons of dose and accuracy were performed. kV CTDIw for 'Head', 'Thorax', 'Pelvis' and 'Image Gently' (in CTDIΦ16cm/CTDIΦ32cm phantoms, respectively) protocols were measured as 4.5 mGy, 5.4 mGy, 19.3 mGy, and 1.1 mGy/0.5 mGy, respectively. Using 'High Quality' mode, MV CTDIw in the CTDIΦ16cm and CTDI Φ32cm phantoms were computed as 84.5 mGy and 63.8 mGy (imaging length = 28 cm), 68.8 mGy and 55.5 mGy (imaging length = 16 cm), respectively, which were about twice of 'Low Dose' mode. The maximum positioning deviation observed on Halcyon was 0.51 mm ('Low Dose' adult thorax), which was lower than that of standard (0.58 mm, 'Pelvis' adult pelvis) and 'Image Gently' kV CBCT (1.57 mm, adult pelvis). Accuracy of 'Image Gently' kV CBCT head & neck and thoracic imaging were clinically acceptable for adults (maximum deviation = 0.54 mm, adult thorax). Complying with Image Gently campaign, dose-efficient protocols should be used for pediatric IGRT, achieving comparable positioning accuracy on the new Halcyon MV CBCT system relative to the conventional kV CBCT.

Early versus late prophylactic cranial irradiation in patients with extensive small cell lung cancer.

OBJECTIVE: Previous studies demonstrated that prophylactic cranial irradiation (PCI) significantly reduced the incidence of brain metastases in patients with extensive disease small cell lung cancer (ED-SCLC). However, the appropriate timing for PCI in treating ED-SCLC is still unclear. This study aimed to compare the effect and safety of early versus late PCI. METHODS: Between November 2011 and July 2016, 103 patients with ED-SCLC were reviewed, receiving appropriate imaging tests to exclude brain metastases prior to cranial irradiation. Of these 103 patients, early PCI was performed in 47 patients and the other 56 patients received late PCI. The primary endpoint was the incidence of brain metastases. The progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were also assessed. RESULTS: Early PCI significantly lowered the risk of brain metastases, as compared to late PCI (p = 0.024). Additionally, multivariate analyses demonstrated that early PCI was a favorable independent predictor of the incidence of brain metastases. The PFS and OS of patients in the early and late PCI groups were comparable (PFS: 8.4 months vs. 7.5 months, p = 0.234; OS: 16.1 months vs. 15.2 months, p = 0.753). The AEs were generally acceptable in both groups. CONCLUSION: To reduce the incidence of brain metastases, early PCI is more effective than late PCI for ED-SCLC patients.

Fully automated searching for the optimal VMAT jaw settings based on Eclipse Scripting Application Programming Interface (ESAPI) and RapidPlan knowledge-based planning.

PURPOSE: Eclipse treatment planning system has not been able to optimize the jaw positions for Volumetric Modulated Arc Therapy (VMAT). The arbitrary and planner-dependent jaw placements define the maximum field size within which multi-leaf-collimator (MLC) sequences can be optimized to modulate the beam. Considering the mechanical constraints of MLC transitional speed and range, suboptimal X jaw settings may impede the optimization or undermine the deliverability. This work searches optimal VMAT jaw settings automatically based on Eclipse Scripting Application Programming Interface (ESAPI) and RapidPlan knowledge-based planning. METHODS AND MATERIALS: Using an ESAPI script, the X jaws of rectal VMAT plans were initially set to conform the planning-target-volume (PTV), and were gradually extended toward the isocenter (PTV center) in 5-7 mm increments. Using these jaw pairs, 592 plans were automatically created for 10 patients and quantitatively evaluated using a comprehensive scoring function. A published RapidPlan model was evoked by ESAPI to generate patient-specific optimization objectives without manual intervention. All candidate plans were first stored as text files to save storage space, and only the best, worst, and conformal plans were consequently recreated for comparison. RESULTS: Although RapidPlan estimates dose-volume histogram (DVH) based on individual anatomy, the geometry-based expected dose (GED) algorithm does not recognize different jaw settings but uses PTV-conformal jaws as default; hence, identical DVHs were observed regardless of planner-defined jaws. Therefore, ESAPI finalized dose-volume calculation and eliminated the plans with unacceptable hotspots before comparison. The plan quality varied dramatically with different jaw settings. Trade-offs among different organs-at-risk (OARs) were collectively considered by the proposed scoring method, which identified the best and worst plans correctly. The plans using conformal jaws were neither the best nor the worst of all candidates. CONCLUSIONS: VMAT plans using optimal jaw locations can be created automatically using ESAPI and RapidPlan. Conformal jaws are not the optimal choice.

An interactive plan and model evolution method for knowledge-based pelvic VMAT planning.

PURPOSE: To test if a RapidPlan DVH estimation model and its training plans can be improved interactively through a closed-loop evolution process. METHODS AND MATERIALS: Eighty-one manual plans (P0 ) that were used to configure an initial rectal RapidPlan model (M0 ) were reoptimized using M0 (closed-loop), yielding 81 P1 plans. The 75 improved P1 (P1+ ) and the remaining 6 P0 were used to configure model M1 . The 81 training plans were reoptimized again using M1 , producing 23 P2 plans that were superior to both their P0 and P1 forms (P2+ ). Hence, the knowledge base of model M2 composed of 6 P0 , 52 P1+ , and 23 P2+ . Models were tested dosimetrically on 30 VMAT validation cases (Pv ) that were not used for training, yielding Pv (M0 ), Pv (M1 ), and Pv (M2 ) respectively. The 30 Pv were also optimized by M2_new as trained by the library of M2 and 30 Pv (M0 ). RESULTS: Based on comparable target dose coverage, the first closed-loop reoptimization significantly (P < 0.01) reduced the 81 training plans' mean dose to femoral head, urinary bladder, and small bowel by 2.65 Gy/15.63%, 2.06 Gy/8.11%, and 1.47 Gy/6.31% respectively, which were further reduced significantly (P < 0.01) in the second closed-loop reoptimization by 0.04 Gy/0.28%, 0.18 Gy/0.77%, 0.22 Gy/1.01% respectively. However, open-loop VMAT validations displayed more complex and intertwined plan quality changes: mean dose to urinary bladder and small bowel decreased monotonically using M1 (by 0.34 Gy/1.47%, 0.25 Gy/1.13%) and M2 (by 0.36 Gy/1.56%, 0.30 Gy/1.36%) than using M0 . However, mean dose to femoral head increased by 0.81 Gy/6.64% (M1 ) and 0.91 Gy/7.46% (M2 ) than using M0 . The overfitting problem was relieved by applying model M2_new . CONCLUSIONS: The RapidPlan model and its constituent plans can improve each other interactively through a closed-loop evolution process. Incorporating new patients into the original training library can improve the RapidPlan model and the upcoming plans interactively.

Photon Optimizer (PO) prevails over Progressive Resolution Optimizer (PRO) for VMAT planning with or without knowledge-based solution.

The enhanced dosimetric performance of knowledge-based volumetric modulated arc therapy (VMAT) planning might be jointly contributed by the patient-specific optimization objectives, as estimated by the RapidPlan model, and by the potentially improved Photon Optimizer (PO) algorithm than the previous Progressive Resolution Optimizer (PRO) engine. As PO is mandatory for RapidPlan estimation but optional for conventional manual planning, appreciating the two optimizers may provide practical guidelines for the algorithm selection because knowledge-based planning may not replace the current method completely in a short run. Using a previously validated dose-volume histogram (DVH) estimation model which can produce clinically acceptable plans automatically for rectal cancer patients without interactive manual adjustment, this study reoptimized 30 historically approved plans (referred as clinical plans that were created manually with PRO) with RapidPlan solution (PO plans). Then the PRO algorithm was utilized to optimize the plans again using the same dose-volume constraints as PO plans, where the line objectives were converted as a series of point objectives automatically (PRO plans). On the basis of comparable target dose coverage, the combined applications of new objectives and PO algorithm have significantly reduced the organs-at-risk (OAR) exposure by 23.49-32.72% than the clinical plans. These discrepancies have been largely preserved after substituting PRO for PO, indicating the dosimetric improvements were mostly attributable to the refined objectives. Therefore, Eclipse users of earlier versions may instantly benefit from adopting the model-generated objectives from other RapidPlan-equipped centers, even with PRO algorithm. However, the additional contribution made by the PO relative to PRO accounted for 1.54-3.74%, suggesting PO should be selected with priority whenever available, with or without RapidPlan solution as a purchasable package. Significantly increased monitor units were associated with the model-generated objectives but independent from the optimizers, indicating higher modulation in these plans. As a summary, PO prevails over PRO algorithm for VMAT planning with or without knowledge-based technique.

Clinical efficacy and safety of limited internal fixation combined with external fixation for Pilon fracture: A systematic review and meta-analysis.

PURPOSE: To compare the clinical efficacy and complications of limited internal fixation combined with external fixation (LIFEF) and open reduction and internal fixation (ORIF) in the treatment of Pilon fracture. METHODS: We searched databases including Pubmed, Embase, Web of science, Cochrane Library and China Biology Medicine disc for the studies comparing clinical efficacy and complications of LIFEF and ORIF in the treatment of Pilon fracture. The clinical efficacy was evaluated by the rate of nonunion, malunion/delayed union and the excellent/good rate assessed by Mazur ankle score. The complications including infections and arthritis symptoms after surgery were also investigated. RESULTS: Nine trials including 498 pilon fractures of 494 patients were identified. The meta-analysis found no significant differences in nonunion rate (RR = 1.60, 95% CI: 0.66 to 3.86, p = 0.30), and the excellent/good rate (RR = 0.95, 95% CI: 0.86 to 1.04, p = 0.28) between LIFEF group and ORIF group. For assessment of infections, there were significant differences in the rate of deep infection (RR = 2.18, 95% CI: 1.34 to 3.55, p = 0.002), and the rate of arthritis (RR = 1.26, 95% CI: 1.03 to 1.53, p = 0.02) between LIFEF group and ORIF group. CONCLUSION: LIFEF has similar effect as ORIF in the treatment of pilon fractures, however, LIFEF group has significantly higher risk of complications than ORIF group does. So LIFEF is not recommended in the treatment of pilon fracture.

Prophylactic cranial irradiation could improve overall survival in patients with extensive small cell lung cancer : A retrospective study.

OBJECTIVE: To evaluate the effect of prophylactic cranial irradiation (PCI) on overall survival (OS) in patients with extensive small cell lung cancer (ESCLC). METHODS: Between April 2005 and May 2014, 204 patients with ESCLC who had any response (according to RECIST 1.1) to initial chemotherapy were reviewed. All patients had undergone appropriate imaging tests to exclude brain metastases before initial chemotherapy. PCI was performed on 45 patients (22.1 %) and the remaining patients (77.9 %) received no such treatment (control group). Primary endpoint was OS. The incidence of brain metastases, brain metastases-free survival (BMFS), and adverse effects were also evaluated. RESULTS: Survival data of the 204 patients were analyzed statistically. PCI significantly prolonged median OS from 12.6 to 16.5 months as compared to the control group (hazard ratio, HR, 0.63; 95 % confidence interval, CI, 0.41 to 0.96; p = 0.033). PCI significantly lowered the risk of brain metastases (HR 0.48; 95 % CI 0.30 to 0.76; p = 0.001). The 1­year incidence of brain metastases was 17.1 and 55.9 % in the PCI and control group, respectively. PCI significantly correlated with the increased median BMFS (p = 0.002). Additionally, multivariate analyses demonstrated that PCI was a favorable independent predictor of OS, BMFS, and the incidence of brain metastases. Acute and chronic adverse effects were generally low grade and well tolerated in patients receiving PCI. CONCLUSION: PCI after any response to initial chemotherapy significantly improved OS of ESCLC patients analyzed in this study.

A dosimetric evaluation of knowledge-based VMAT planning with simultaneous integrated boosting for rectal cancer patients.

RapidPlan, a commercial knowledge-based optimizer, has been tested on head and neck, lung, esophageal, breast, liver, and prostate cancer patients. To appraise its performance on VMAT planning with simultaneous integrated boosting (SIB) for rectal cancer, this study configured a DVH (dose-volume histogram) estimation model consisting 80 best-effort manual cases of this type. Using the model-generated objectives, the MLC (multileaf collimator) sequences of other 70 clinically approved plans were reoptimized, while the remaining parameters, such as field geometry and photon energy, were maintained. Dosimetric outcomes were assessed by comparing homogeneity index (HI), conformal index (CI), hot spots (volumes receiving over 107% of the prescribed dose, V107%), mean dose and dose to the 50% volume of femoral head (Dmean_FH and D50%_FH), and urinary bladder (Dmean_UB and D50%_UB), and the mean DVH plotting. Paired samples t-test or Wilcoxon signed-rank test suggested that comparable CI were achieved by RapidPlan (0.99± 0.04 for PTVboost, and 1.03 ± 0.02 for PTV) and original plans (1.00 ± 0.05 for PTVboost and 1.03 ± 0.02 for PTV), respectively (p > 0.05). Slightly improved HI of planning target volume (PTVboost) and PTV were observed in the RapidPlan cases (0.05 ± 0.01 for PTVboost, and 0.26 ± 0.01 for PTV) than the original plans (0.06 ± 0.01 for PTVboost and 0.26 ± 0.01 for PTV), p < 0.05. More cases with positive V107% were found in the original (18 plans) than the RapidPlan group (none). RapidPlan significantly reduced the D50%_FH (by 1.53 Gy / 9.86% from 15.52 ± 2.17 to 13.99± 1.16 Gy), Dmean_FH (by 1.29 Gy / 7.78% from 16.59± 2.07 to 15.30 ± 0.70 G), D50%_UB (by 4.93 Gy / 17.50% from 28.17 ± 3.07 to 23.24± 2.13 Gy), and Dmean_UB (by 3.94Gy / 13.43% from 29.34 ± 2.34 to 25.40 ± 1.36 Gy), respectively. The more concentrated distribution of RapidPlan data points indicated an enhanced consis-tency of plan quality.

A comparative study of identical VMAT plans with and without jaw tracking technique.

The unwanted radiation transmission through the multileaf collimators could be reduced by the jaw tracking technique which is commercially available on Varian TrueBeam accelerators. On the basis of identical plans, this study aims to investigate the dosimetric impact of jaw tracking on the volumetric-modulated arc therapy (VMAT) plans. Using Eclipse treatment planning system (TPS), 40 jaw-tracking VMAT plans with various tumor volumes and shapes were optimized. Fixed jaw plans were created by editing the jaw coordinates of the jaw-tracking plans while other parameters were identical. The deliverability of this artificial modification was verified using COMPASS system via three-dimentional gamma analysis between the measurement-based reconstruction and the TPS-calculated dose distribution. Dosimetric parameters of dose-volume histogram (DVH) were compared to assess the improvement of dose sparing for organs at risk (OARs) in jaw-tracking plans. COMPASS measurements demonstrated that over 96.9% of structure volumes achieved gamma values less than 1.00 at criteria of 3 mm/3%. The reduction magnitudes of maximum and mean dose to various OARs ranged between 0.06% ~ 6.76% (0.04 ~ 7.29 Gy) and 0.09% ~ 7.81% (0.02 ~ 2.78 Gy), respectively, using jaw tracking, agreeing with the disparities of radiological characteristics between MLC and jaws. Jaw tracking does not change the delivery efficiency and total monitor units. The dosimetric comparison of VMAT plans with and without jaw tracking confirms the physics hypotheses that reduced transmission through tracking jaws will reduce doses to OARs without sacrificing the target dose coverage because it is meant to be covered by radiation beams going through the opening.

[Progress in study on endocannabinoids and cannabinoid receptors in the treatment for neuropathic pain].

Endocannabinoids and cannabinoid receptors are expressed in various central pain modulation regions. They maintain in dynamic changes in the expression level and distribution under different pathological and physiological conditions. These changes possess advantage as well as disadvantage. Exogenous administration of endocannabinoids exerts analgesic effect in different pain models, which is mainly mediated by the cannabinoid CB1 and CB2 receptors. Inhibition of enzymes for degrading endocannabinoids in different pain models also shows analgesic effect due to the increased local levels of endocannabinoids.

Cognition, affect, and behavioural changes among university students after 10 new guidelines were issued in China: An exploratory study.

Objectives: Since late 2019, the coronavirus disease 2019 (COVID-19) epidemic has become a common public health concern globally. China has entered a new phase of prevention and control with the implementation of the 10 new guidelines epidemic prevention policy in early December 2022. The resurgence of the outbreak may cause negative consequences on the behaviour of university students. This study aimed to assess the relationship between cognition, affect, and behavioural changes among university students and the related influencing factors after 10 new guidelines were issued, as well as the difficulties or concerns encountered in the current epidemic prevention process. It also provides a reference for the government to formulate targeted epidemic prevention strategies. Methods: This study is a cross-sectional investigation. Self-designed questionnaires were distributed to students of a university in Hangzhou between December 25, 2022, and March 13, 2023, using convenience and snowball sampling methods for online surveys. Data analysis involved descriptive analysis, non-parametric tests, correlation, multiple linear regression, and content analyses. Results: University students had a moderate to high level of cognition about COVID-19 and a medium level of affect. However, the level of behavioural changes was low and the average score was 2.33 (2.00, 3.00). Multiple linear regression analysis revealed that female sex, higher grade, medical specialty, affective factor, and cognitive factor were influencing factors of behavioural changes, which accounted for 35.7% of the variance in behavioural change. Difficulties or concerns included apprehension (84.8%), lack of information (39.3%), and uncertainty about the future (55.1%). Conclusions: The prevention behaviour of university students has slackened. Evidence-based tailored policy development is indicated. This study suggested that schools and the government can improve the effectiveness of epidemic prevention among university students by adjusting the strategy of epidemic prevention policy formulation, broadening the channels of epidemic prevention information dissemination, and improving the mechanism of "government-community-school-family" collaborative governance.

Repeated (S)-ketamine administration ameliorates the spatial working memory impairment in mice with chronic pain: role of the gut microbiota-brain axis.

Chronic pain is commonly linked with diminished working memory. This study explores the impact of the anesthetic (S)-ketamine on spatial working memory in a chronic constriction injury (CCI) mouse model, focusing on gut microbiome. We found that multiple doses of (S)-ketamine, unlike a single dose, counteracted the reduced spontaneous alteration percentage (%SA) in the Y-maze spatial working memory test, without affecting mechanical or thermal pain sensitivity. Additionally, repeated (S)-ketamine treatments improved the abnormal composition of the gut microbiome (ß-diversity), as indicated by fecal 16S rRNA analysis, and increased levels of butyrate, a key gut - brain axis mediator. Protein analysis showed that these treatments also corrected the upregulated histone deacetylase 2 (HDAC2) and downregulated brain-derived neurotrophic factor (BDNF) in the hippocampi of CCI mice. Remarkably, fecal microbiota transplantation from mice treated repeatedly with (S)-ketamine to CCI mice restored %SA and hippocampal BDNF levels in CCI mice. Butyrate supplementation alone also improved %SA, BDNF, and HDAC2 levels in CCI mice. Furthermore, the TrkB receptor antagonist ANA-12 negated the beneficial effects of repeated (S)-ketamine on spatial working memory impairment in CCI mice. These results indicate that repeated (S)-ketamine administration ameliorates spatial working memory impairment in CCI mice, mediated by a gut microbiota - brain axis, primarily through the enhancement of hippocampal BDNF - TrkB signaling by butyrate.

Mechanistic modelling of relative biological effectiveness of carbon ion beams and comparison with experiments.

Objective.Relative biological effectiveness (RBE) plays a vital role in carbon ion radiotherapy, which is a promising treatment method for reducing toxic effects on normal tissues and improving treatment efficacy. It is important to have an effective and precise way of obtaining RBE values to support clinical decisions. A method of calculating RBE from a mechanistic perspective is reported.Approach.Ratio of dose to obtain the same number of double strand breaks (DSBs) between different radiation types was used to evaluate RBE. Package gMicroMC was used to simulate DSB yields. The DSB inductions were then analyzed to calculate RBE. The RBE values were compared with experimental results.Main results.Furusawa's experiment yielded RBE values of 1.27, 2.22, 3.00 and 3.37 for carbon ion beam with dose-averaged LET of 30.3 keVµm-1, 54.5 keVµm-1, 88 keVµm-1and 137 keVµm-1, respectively. RBE values computed from gMicroMC simulations were 1.75, 2.22, 2.87 and 2.97. When it came to a more sophisticated carbon ion beam with 6 cm spread-out Bragg peak, RBE values were 1.61, 1.63, 2.19 and 2.36 for proximal, middle, distal and distal end part, respectively. Values simulated by gMicroMC were 1.50, 1.87, 2.19 and 2.34. The simulated results were in reasonable agreement with the experimental data.Significance.As a mechanistic way for the evaluation of RBE for carbon ion radiotherapy by combining the macroscopic simulation of energy spectrum and microscopic simulation of DNA damages, this work provides a promising tool for RBE calculation supporting clinical applications such as treatment planning.

Efficacy of high-dose-rate brachytherapy with different radiation source activities among cervical cancer patients and risk factors for long-term outcomes: A 6-year retrospective study.

PURPOSE: This study aimed to assess the impact of dose rates due to natural decay of Iridium-192 sources and the risk factors of clinical outcomes for cervical cancer patients treated with high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS: Four ninety-four patients were divided into relatively-high-radioactive (rHR), relatively-medium-radioactive (rMR), and relatively-low-radioactive (rLR) groups for retrospective treatment response comparison. The short-term outcomes were evaluated using the 1-month /3-month follow-up results based on RECIST 1.1. Local recurrence-free survival (LRFS) and metastatic recurrence-free survival (MRFS) were selected as long-term outcomes. A class of transformation models with adaptive lasso was applied to assess the risk factors of long-term outcomes. RESULTS: No significant difference was identified in short- or long-term outcomes of different radioactive groups. Subgroup analyses demonstrated similar findings. In multivariate factor analysis, advanced stage was significantly associated with higher risk of local recurrence and metastatic recurrence (HR = 1.66, 95%confidence interval [CI] = 1.14-2.43, p = 0.008; HR = 1.57, 95%CI = 1.23-2.00, p < 0.001). Significant associations were observed between local recurrence and pathology, and between metastatic recurrence and pre-treatment serum indices, respectively (HR = 8.62, 95%CI = 2.28-32.60, p = 0.002; HR = 1.98, 95%CI=1.20-2.26, p = 0.008). CONCLUSIONS: Overall, there was no significant difference in long- or short-term efficacy of the HDR brachytherapy among the groups with different levels of activity of radiation sources. Stage, pathology, and pretreatment serum indices were crucial factors that affected the long-term outcomes.

Bradykinin protects nucleus pulposus cells from tert-butyl hydroperoxide-induced damage and delays intervertebral disc degeneration.

Intervertebral disc degeneration (IVDD) is a leading cause of degenerative spinal disorders, involving complex biological processes. This study investigates the role of the kallikrein-kinin system (KKS) in IVDD, focusing on the protective effects of bradykinin (BK) on nucleus pulposus cells (NPCs) under oxidative stress. Clinical specimens were collected, and experiments were conducted using human and rat primary NPCs to elucidate BK's impact on tert-butyl hydroperoxide (TBHP)-induced oxidative stress and damage. The results demonstrate that BK significantly inhibits TBHP-induced NPC apoptosis and restores mitochondrial function. Further analysis reveals that this protective effect is mediated through the BK receptor 2 (B2R) and its downstream PI3K/AKT pathway. Additionally, BK/PLGA sustained-release microspheres were developed and validated in a rat model, highlighting their potential therapeutic efficacy for IVDD. Overall, this study sheds light on the crucial role of the KKS in IVDD pathogenesis and suggests targeting the B2R as a promising therapeutic strategy to delay IVDD progression and promote disc regeneration.