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Structural analysis and construction control of staged construction process is a major subject for modern long-span bridges. This paper introduces the concept of stress-free-state variable of structural elements and deduces the mechanical equilibrium equations and geometric shape governing equations for staged construction structures utilizing the minimum potential energy theorem. As the core of stress-free-state theory, the two aforementioned equations demonstrate following principles, 1) when the stress-free-state variable of a structural element is set, the internal force and deformation of the element are unique at the completion state of the structure regardless of its construction process; 2) the stress-free length of a cable is independent of its external loads, change in stress-free length of the cable corresponds to a unique variation of the cable force when load is constant; and 3) the internal force of a structural element can be independent from its geometric shape within the completion state of a staged construction structure through an active manipulation of stress-free-state variables of the element. Stress-free-state theory establishes the stage-to-stage and stage-to-completion relationships for staged construction bridges, provides a direct and efficient method for theoretical calculations and a flexible and convenient approach for the control of staged construction, and makes parallel construction and auto-filtering of thermal and temporary loading effect possible.

Extreme temperature events (ETEs) pose increasing risks for surgical patients, who may be vulnerable to temperature fluctuations. The associations between ETEs and intraoperative hypotension (IOH) remain understudied. We conducted a retrospective cohort analysis on patients undergoing major surgery between 2015 and 2023 at three large academic centers. ETEs were defined using percentile-based temperature thresholds and duration. Heat waves were periods of at least 3 consecutive days with daily average temperatures at or above the 95th or 97.5th percentiles of the previous 30 days, while cold spells were periods with temperatures at or below the 5th or 2.5th percentiles. The primary outcome was IOH ≥10 min, defined as a mean arterial pressure < 65 mmHg for ≥10 min. Secondary outcome was the duration of IOH ≥10 min. Logistic regression and generalized linear models were used to assess associations, adjusting for relevant covariates. Among 276,515 eligible subjects, 48,023 were exposed to heat waves, 42,615 to cold spells, and 185,877 remained unexposed. The presence of an arterial catheter was noted in 30.31 % of the patients. Heat waves were associated with a reduced risk of IOH lasting ≥10 min (adjusted odds ratio [aOR], 0.80; 95 % confidence interval [CI], 0.76–0.84; P < 0.001). The total difference in IOH duration across the range of 30-day average temperatures from 0 to 30 °C was approximately 4 min, highlighting the modest magnitude of the effect. Cold spells were associated with an increased IOH risk, with the strongest association observed for cold spells defined by the 2.5th percentile lasting 4 days (aOR, 1.31; 95 % CI, 1.24–1.39; P < 0.001). The magnitude of risk also increased with longer IOH duration. Restricted cubic spline analyses further revealed non-linear associations with the duration of IOH for mean temperature 30 days prior to admission (p-nonlinearity = 0.036). ETEs were associated with IOH, with heat waves reducing risk and cold spells increasing risk. These results provide new evidence on the physiological effects of environmental temperature extremes in the perioperative setting. •Warm weather promotes thermoregulatory vasodilation whereas cold weather promotes vasoconstriction.•Ambient temperatures during the 30 days before surgery may therefore reduce or increase intraoperative hypotension.•Extreme heat slightly reduced the odds for intraoperative hypotension whereas extreme cold slightly increased the odds.•Both effects appear small compared with other risk factors for hypotension.

Background Different approach ultrasound-guided superior laryngeal nerve block was used to aid awake intubation, but little is known which approach was superior. We aimed to compare the parasagittal and transverse approaches for ultrasound-guided superior laryngeal nerve block in adult patients undergoing awake intubation. Methods Fifty patients with awake orotracheal intubation were randomized to receive either a parasagittal or transverse ultrasound-guided superior laryngeal nerve block. The primary outcome was patient’s quality of airway anesthesia grade during insertion of the tube into the trachea. The patients’ tube tolerance score after intubation, total procedure time, mean arterial pressure, heart rate, Ramsay sedation score at each time point, incidence of sore throat both 1 h and 24 h after extubation, and hoarseness before intubation, 1 h and 24 h after extubation were documented. Results Patients’ quality of airway anesthesia was significantly better in the parasagittal group than in the transverse group (median grade[IQR], 0 [0–1] vs. 1 [0–1], P  = 0.036). Patients in the parasagittal approach group had better tube tolerance scores (median score [IQR],1[1–1] vs. 1 [1–1.5], P  = 0.042) and shorter total procedure time (median time [IQR], 113 s [98.5–125.5] vs. 188 s [149.5–260], P  < 0.001) than those in the transverse approach group. The incidence of sore throat 24 h after extubation was lower in the parasagittal group (8% vs. 36%, P  = 0.041). Hoarseness occurred in more than half of the patients in parasagittal group before intubation (72% vs. 40%, P  = 0.023). Conclusions Compared to the transverse approach, the ultrasound-guided parasagittal approach showed improved efficacy in terms of the quality of airway topical anesthesia and shorter total procedure time for superior laryngeal nerve block. Trial registration This prospective, randomized controlled trial was approved by the Ethics Committee of Nanjing First Hospital (KY20220425-014) and registered in the Chinese Clinical Trial Registry (19/6/2022, ChiCTR2200061287) prior to patient enrollment. Written informed consent was obtained from all participants in this trial.

To find satisfactory treatment strategies for neuropathic pain syndromes, the cellular mechanisms should be illuminated. Central sensitization is a generator of pain hypersensitivity, and is mainly reflected in neuronal hyperexcitability in pain pathway. Neuronal excitability depends on two components, the synaptic inputs and the intrinsic excitability. Previous studies have focused on the synaptic plasticity in different forms of pain. But little is known about the changes of neuronal intrinsic excitability in neuropathic pain. To address this question, whole-cell patch clamp recordings were performed to study the synaptic transmission and neuronal intrinsic excitability 1 week after spared nerve injury (SNI) or sham operation in male C57BL/6J mice. We found increased spontaneous excitatory postsynaptic currents (sEPSC) frequency in layer II/III pyramidal neurons of anterior cingulate cortex (ACC) from mice with neuropathic pain. Elevated intrinsic excitability of these neurons after nerve injury was also picked up, which was reflected in gain of input-output curve, inter-spike interval (ISI), spike threshold and Refractory period (RP). Besides firing rate related to neuronal intrinsic excitability, spike timing also plays an important role in neural information processing. The precision of spike timing measured by standard deviation of spike timing (SDST) was decreased in neuropathic pain state. The electrophysiological studies revealed the elevated intrinsic excitation in layer II/III pyramidal neurons of ACC in mice with neuropathic pain, which might contribute to central excitation.

The adverse effects of anesthetics on elderly people, especially those with brain diseases are very concerning. Whether inhaled anesthetics have adverse effects on Alzheimer's disease (AD), which is the most common form of dementia with brain degenerative changes, remains controversial. Autophagy, a crucial biological degradation process, is extremely important for the pathogenesis of AD. In this study, the inhaled anesthetic sevoflurane elicited many enlarged autolysosomes and impaired the overall autophagic degradation in the hippocampus of an AD mouse model, which is involved in the accumulation of amyloid-β (Aβ) and spatial learning deficits. However, rapamycin treatment counteracted all these effects. The results suggested that inhaled anesthetics may accelerate the pathological process of AD, and enlarged autolysosomes may be a new marker for prediction and diagnosis of the neurotoxicity of anesthetics in AD.

Background Adherence to a healthy lifestyle is associated with substantially lower risks of mortality from all causes, cardiovascular diseases, and cancer in white populations. However, little is known about the health benefits among non-white populations. Also, no previous studies have focused on respiratory disease mortality in both white and non-white populations. We assessed the relationships between a combination of healthy lifestyle factors and multiple death outcomes in Chinese adults. Methods This study included 487,198 adults aged 30–79 years from the China Kadoorie Biobank without heart disease, stroke, and cancer at study enrolment. We defined five healthy lifestyle factors as never smoking or smoking cessation not due to illness; non-daily drinking or moderate alcohol drinking; median or higher level of physical activity; a diet rich in vegetables, fruits, legumes and fish, and limited in red meat; a body mass index of 18.5 to 27.9 kg/m 2 and a waist circumference < 90 cm (men)/85 cm (women). Cox regression was used to produce adjusted hazard ratios (HRs) relating these healthy lifestyle factors to all-cause and cause-specific mortality. Results During a median follow-up of 10.2 years (IQR 9.2–11.1), we documented 37,845 deaths. After multivariable adjustment, the number of healthy lifestyle factors exhibited almost inverse linear relationships with the risks of all-cause and cause-specific mortality. Compared with participants without any healthy factors, the hazard ratio of participants with five healthy factors was 0.32 [95% confidence interval (CI): 0.28, 0.37] for all-cause mortality. The corresponding HRs in specific cause of death were 0.42 (95% CI: 0.26, 0.67) for ischaemic heart disease, 0.21 (95% CI: 0.09, 0.49) for ischaemic stroke, 0.37 (95% CI: 0.22, 0.60) for haemorrhage stroke, 0.36 (95% CI: 0.29, 0.45) for cancer, 0.26 (95% CI: 0.14, 0.48) for respiratory diseases, and 0.29 (95% CI: 0.22, 0.39) for other causes. Theoretically, 38.5% (95% CI: 33.0, 43.8%) of all-cause mortality was attributable to nonadherence to a healthy lifestyle, and the proportions of preventable deaths through lifestyle modification ranged from 26.9 to 47.9% for cause-specific mortality. Conclusions Adherence to a healthy lifestyle was associated with substantially lower risks of all-cause, cardiovascular, respiratory, and cancer mortality in Chinese adults. Promotion of a healthy lifestyle may considerably reduce the burden of non-communicable diseases in China.

Autophagy allows cancer cells to respond changes in nutrient status by degrading and recycling non-essential intracellular contents. Inhibition of autophagy combined with nutrient deprivation is an effective strategy to treat cancer. Pain is a primary determinant of poor quality of life in advanced cancer patients, but there is currently no satisfactory treatment. In addition, effective treatment of cancer does not efficiently relieve cancer pain, but may increase pain in many cases. Hence, few studies focus on simultaneous cancer therapy and pain relief, and made this situation even worse. : Ropivacaine was loaded into tumor-active targeted liposomes. The cytotoxicity of ropivacaine-based combination therapy in B16 and HeLa cells were tested. Moreover, a mice model of cancer pain which was induced by inoculation of melanoma near the sciatic nerve was constructed to assess the cancer suppression and pain relief effects of ropivacaine-based combination therapy. : Ropivacaine and ropivacaine-loaded liposomes (Rop-DPRL) were novelly found to damage autophagic degradation. Replicated administration of Rop-DPRL and calorie restriction (CR) could efficiently repress the development of tumor. In addition, administration of Rop-DPRL could relieve cancer pain with its own analgestic ability in a short duration, while repeated administration of Rop-DPRL and CR resulted in continuous alleviation of cancer pain through reduction of VEGF-A levels in advanced cancer mice. Further, dual inhibition of phosphorylation of STAT3 at Tyr705 and Ser727 by Rop-DPRL and CR contribute to the reduction of VEGF-A. : Combination therapy with Rop-DPRL and nutrient deprivation simultaneously suppresses cancer growth and relieves cancer pain.

Mitochondrial quality control is tightly associated with aging‐related neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). Previous studies reported that ALS/FTD‐associated protein p62 drives “mitochondrial clustering” (perinuclear clustering of fragmented and swollen mitochondria) during PINK1/Parkin‐mediated mitophagy, but the underlying molecular mechanism, especially the precise role of p62 in mitochondrial clustering during mitophagy and the potential relationship between the mitochondrial quality control mediated by p62 and disease pathogenesis of ALS/FTD, remains unclear. Here, using cell biology in combination with an optogenetic tool, we show that the phase separation (condensation) of p62 mediates the clustering of damaged mitochondria to form “grape‐like” clusters during PINK1/Parkin‐mediated mitophagy, which is tightly associated with aging‐related neurodegenerative diseases. In addition, our data suggest this mitochondrial clustering process is an arrest mechanism driven by p62 condensation (beyond the function of other autophagy receptors in mitophagy), which acts as a “brake” to reduce the surface area of dysfunctional mitochondria within cytoplasm for minimizing mitochondrial turnover in cells. Moreover, ALS/FTD‐related pathological mutations perturb p62 condensation, thereby inhibiting mitochondrial clustering and destroying the “brake” machinery of mitochondrial quality control. Together, our data highlight how p62 condensation modulates organelle quality control in cell biology, and the important role of p62 condensation in both physiology and pathology. In normal PINK1/Parkin‐mediated mitophagy, unlike OPTN (the mitophagy receptor that mediates ATG8‐labeled autophagosome recruitment onto ubiquitinated mitochondria), p62 mediates the clustering of ubiquitinated mitochondria to form the “grape‐like” aggregates with ubiquitin. Under aging‐related neurodegenerative disease conditions, pathogenic mutants perturb p62 condensation, thereby destroying mitochondrial aggregation and impairing mitochondrial quality control.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and β-amyloid (Aβ) plays a leading role in the pathogenesis of AD. The transcription factor EB (TFEB), a main regulating factor of autophagy and lysosome biosynthesis, is involved in the pathogenesis of AD by regulating autophagy-lysosomal pathways. To date, the choice of anesthetics during surgery in patients with neurodegenerative diseases and evaluation of the effects and underlying mechanisms in these patients have rarely been reported. In this study, the HEK293-APP cells overexpressing APP and Hela cells were used. The cells were treated with midazolam at different concentrations and at different times, then lysosomes were stained by lysotracker and their morphology was observed under a fluorescence microscope. The number and size of lysosomes were analyzed using the ImageJ software. The levels of TFEB in the nucleus and APP-cleaved intracellular proteins were detected by nuclear separation and Western Blot. Finally, ELISA was used to detect the levels of Aβ40 and Aβ42 in the cells after drug treatment. We found that 30 μM midazolam decreased the number of lysosomes and increased its size in HEK293 and HeLa cells. However, 15 μM midazolam transiently disturbed lysosomal homeostasis at 24 h and recovered it at 36 h. Notably, there was no significant difference in the extent to which lysosomal homeostasis was disturbed between treatments of different concentrations of midazolam at 24 h. In addition, 30 μM midazolam prevents the transport of TFEB to the nucleus in either normal or starved cells. Finally, the intracellular C-terminal fragment β (CTFβ), CTFα, Aβ40 and Aβ42 levels were all significantly elevated in 30 μM midazolam-treated HKE293-APP cells. Collectively, the inhibition of TFEB transport to the nucleus may be involved in midazolam-disturbed lysosomal homeostasis and its induced Aβ accumulation . The results indicated the risk of accelerating the pathogenesis of AD by midazolam and suggested that TFEB might be a candidate target for reduction of midazolam-dependent neurotoxicity.