Decoding aging-dependent regenerative decline across tissues at single-cell resolution.

Regeneration across tissues and organs exhibits significant variation throughout the body and undergoes a progressive decline with age. To decode the relationships between aging and regenerative capacity, we conducted a comprehensive single-cell transcriptome analysis of regeneration in eight tissues from young and aged mice. We employed diverse analytical models to study tissue regeneration and unveiled the intricate cellular and molecular mechanisms underlying the attenuated regenerative processes observed in aged tissues. Specifically, we identified compromised stem cell mobility and inadequate angiogenesis as prominent contributors to this age-associated decline in regenerative capacity. Moreover, we discovered a unique subset of Arg1+ macrophages that were activated in young tissues but suppressed in aged regenerating tissues, suggesting their important role in age-related immune response disparities during regeneration. This study provides a comprehensive single-cell resource for identifying potential targets for interventions aimed at enhancing regenerative outcomes in the aging population.

Exosomal transfer of microRNA-590-3p between renal tubular epithelial cells after renal ischemia-reperfusion injury regulates autophagy by targeting TRAF6.

BACKGROUND: Acute kidney injury (AKI) is a common complication in patients, especially elderly patients, who undergo cardiac surgery with cardiopulmonary bypass. Studies have indicated a protective role of autophagy in AKI. However, the mechanisms underlying the regulatory effect of autophagy in AKI among patients undergoing cardiac surgeries are poorly understood. In this study, we aimed to test the hypothesis that exosomal microRNAs (miRNAs) regulate autophagy in tubular epithelial cells after AKI. METHODS: Plasma exosomal RNA was extracted from young and elderly AKI patients undergoing cardiac surgery, and the miRNAs expression during the perioperative period were analyzed using next-generation sequencing. The screened miRNAs and their target genes were subjected to gene oncology function and Kyoto Encyclopedia of Genes and Genome enrichment analyses. Renal tubular epithelial cell line (HK-2 cells) was cultured and hypoxia/reoxygenation (H/R) model was established, which is an in vitro renal ischemia/reperfusion (I/R) model. We used Western blot analysis, cell viability assay, transfection, luciferase assay to investigate the mechanisms underlying the observed increases in the levels of renal I/R injury-mediated exosomal miRNAs and their roles in regulating HK-2 cells autophagy. RESULTS: miR-590-3p was highly enriched in the plasma exosomes of young AKI patients after cardiac surgery. Increased levels of miR-590-3p led to the increases in the expression of autophagy marker proteins, including Beclin-1 and microtubule associated protein 1 light chain 3 beta (LC3II), and prolonged the autophagic response in HK-2 cells after H/R treatment. These effects were achieved mainly via increases in the exosomal miR-590-3p levels, and the tumor necrosis factor receptor-associated factor 6 protein was shown to play a key role in I/R injury-mediated autophagy induction. CONCLUSION: Exosomes released from HK-2 cells after renal I/R injury regulate autophagy by transferring miR-590-3p in a paracrine manner, which suggests that increasing the miR-590-3p levels in HK-2 cell-derived exosomes may increase autophagy and protect against kidney injury after renal I/R injury.

Corrigendum: Moderate and Deep Hypothermic Circulatory Arrest Have Comparable Effects on Severe Systemic Inflammatory Response Syndrome After Total Aortic Arch Replacement in Patients With Type A Aortic Dissection.

[This corrects the article DOI: 10.3389/fsurg.2021.758854.].

The antidepressant potential of lactobacillus casei in the postpartum depression rat model mediated by the microbiota-gut-brain axis.

Lactobacillus casei, a kind of probiotic, was reported as antidepressant effects. However, little is known about the effect of Lactobacillus casei on postpartum depression (PPD). In this study, we investigated the effects of Lactobacillus casei in improving PPD and potential mechanisms. Four hours of daily maternal separation from postnatal day 2 to day 21 was performed to establish the PPD model in rats. From postnatal day 2 to day 28, rats were gavage-fed with an equal volume of normal saline, Lactobacillus casei (8 × 108 CFU/kg/day), or paroxetine (1.8 mg/kg/day), respectively. Rat behaviors were measured using the sucrose preference test, the elevated plus maze, the forced swim test, and the tail suspension test. Changes in gut microbiota were detected by real-time fluorescence quantitative PCR. Administration of Lactobacillus casei improved depressive-like behaviors, intestinal microflora, and oxidative stress in PPD model rats. Western Blot or HPLC assays showed that Lactobacillus casei intervention reversed the changes of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartic acid receptor 1 (NR1), ERK1/2, and monoamines in the brain of PPD rats. These results suggest that Lactobacillus casei could improve PPD through altering gut microbiota composition, brain monoamines and oxidative stress, which may be associated with the regulation of the BDNF-ERK1/2 pathway.

Moderate and Deep Hypothermic Circulatory Arrest Have Comparable Effects on Severe Systemic Inflammatory Response Syndrome After Total Aortic Arch Replacement in Patients With Type A Aortic Dissection.

Background: The objective of this study was to compare the incidence of severe systemic inflammatory response syndrome (sSIRS) after total aortic arch replacement between patients who underwent moderate hypothermic circulatory arrest (MHCA) and those who underwent deep hypothermic circulatory arrest (DHCA). Methods: At Fuwai Hospital, 600 patients who underwent total aortic arch replacement with MHCA or DHCA from January 2013 to December 2016 were consecutively enrolled and divided into DHCA (14.1-20.0°C) and MHCA (20.1-28.0°C) groups. Preliminary statistical analysis revealed that some baseline indicators differed between the two groups; therefore, propensity score matching (PSM) was used to balance the covariates. Post-operative sSIRS as the primary outcome was compared between the groups both before and after PSM. Results: A total of 275 (45.8%) patients underwent MHCA, and 325 (54.2%) patients underwent DHCA. After PSM analysis, a total of 191 matched pairs were obtained. The overall incidence of sSIRS was 27.3%. There was no significant difference in post-operative sSIRS between the MHCA group and the DHCA group in either the overall cohort or the PSM cohort (no-PSM: P = 0.188; PSM: P = 0.416); however, post-operative sSIRS was increased by ~4% in the DHCA group compared with the MHCA group in both the no-PSM and PSM cohorts (no-PSM: 29.5 vs. 24.7%; PSM: 29.3 vs. 25.1%). Both before and after PSM, the rates of gastrointestinal hemorrhage and pulmonary infection and post-operative length of stay were significantly increased in the DHCA group compared with the MHCA group (P < 0.05), and the remaining secondary outcomes were not significantly different between the groups. Conclusions: MHCA and DHCA are associated with comparable incidences of sSIRS in patients following total aortic arch replacement for type A aortic dissection. However, the MHCA group had a shorter cardiopulmonary bypass time, a shorter post-operative length of stay and lower pulmonary infection and gastrointestinal hemorrhage rates than the DHCA group. We cautiously recommend the use of MHCA for most total arch replacements in patients with type A aortic dissection.

[Preliminary experimental study on the influence of different tidal volume and frequency of normal minute ventilation on the dynamic changes of carotid blood oxygen in living goats].

Objective: On the basis of preliminarily verifying the use of ultra-fast reaction polymer matrix optical fiber oxygen sensor and its measuring system to record the continuous and dynamic changes of carotid artery oxygen partial pressure (PaO2), in order to analyze and discuss the influence of lung ventilation on the continuous and dynamic changes of PaO2, we designed a whole animal experimental study in vivo. Methods: Four hybrid goats were selected, and the skin was cut and exposed directly under general anesthesia and tracheal intubation. The oxygen sensor, connected with the measuring system, was inserted directly into the left carotid artery to continuously record the dynamic changes of PaO2. With normal minute ventilation,mechanical ventilation is implemented through three tidal volumes: normal tidal volume (VT=15 ml/kg, Rf=20 bpm), half tidal volume (halved VT, doubled Rf) and double tidal volume (doubled VT, halved Rf). Each tidal volume was stable for 10~15 min respectively. We analyzed and calculated the average values of PaO2, the fluctuation magnitudes of PaO2 changes between breaths of last 180 s and the delay times of lung-carotid artery were. We analyzed the effects of different tidal volumes. Results: The heart rate and blood pressure of living goats were maintained stable during the mechanical ventilation experiment with normal ventilation volume Lung-carotid artery delay time is 1.4~1.8 s (about 3 heartbeats at this time). Under normal tidal volume of mechanical ventilation, the average value of PaO2 was (102.94±2.40, 99.38~106.16) mmHg, and the fluctuation range was (21.43±1.65, 19.21~23.59) mmHg, accounting for (20.80± 1.34, 18.65~22.22)% of the average value. Under the condition of halving tidal volume, the average value of PaO2 was maintained at (101.01±4.25, 94.09~105.66) mmHg, which was slightly decreased but not significant (P>0.05 compared with normal mechanical ventilation), but the fluctuation range of PaO2 was significantly reduced to (18.14±1.43, 16.46~20.05) mmHg, accounting for 17.5% of the average value. Under double tidal volume mechanical ventilation, although the average value of PaO2 increased slightly remained at (106.42±4.74, 101.19~114.08) mmHg (P>0.05 compared with normal mechanical ventilation and P<0.05 compared with half tidal volume mechanical ventilation), the fluctuation magnitude of PaO2 increased significantly to (26.58±1.88, 23.46~28.46)mmHg. Conclusion: Inspiration and expiration of normal lung ventilation are the initial factors for the increase and decrease of PaO2 in carotid artery. Under normal ventilation, halving tidal volume and doubling tidal volume significantly changed the fluctuation magnitude of PaO2, but the average value of PaO2 changed only slightly, while the lung-carotid delay time was similar.

[Ultra-fast response polymer optical fiber oxygen measurement device and its preliminary experimental report on continuous dynamic change of arterial oxygen partial pressure under mechanical ventilation in living animals].

Objective: We tried to implant the ultra-fast polymer optical fiber chemical oxygen sensor （POFCOS） into arterial blood vessel,connect with photoelectric conversion measurement system to record the continuous dynamic rapid changes of arterial PO2(PaO2) in whole living animals. It should be the experimental evidence for the new theory of holistic integrative physiology and medicine(HIPM) forexplain the mechanism of respiratory control and regulation in whole circusof respiration-circulation-metabolism. Methods: ①Fabrication of ultrafast POFCOS, calibration and its measuring system: The distal part of 2 m optical fiber was heated and pulled until it became a tapered tip. After cleaning and drying, the tip of 1 mm tapered optical fiber was dip-coated into the luminophore doped polymer solution, then was slowly pumped out while solvent was quickly evaporated to form an oxygen sensing tip, which was dried at room temperature for 24 hours. ②Animal experiments: Under general anesthesia and intubation, goatwas mechanically ventilated with 40%~60% oxygen. We exposed both right and left carotid arteries and the left femoral artery by skin cutting, and inserted the POFCOS directly into the arteries via indwelling catheter. The end of POFCOS were connected to the personal computer through optical fiber, excitation and detection Y-type optical fiber coupler through photoelectric conversion, so as we can realize the continuous dynamic response of living goat carotid PaO2 under mechanical ventilation. We mainly analyzed the intra-breath wave-form alternate increase and decrease of PaO2 and their time delay between lung and carotid arteries.We completes breathing control whole loop to explain the mechanism of mutual breathing and the switching of inspiration and exhalation. Results: The POFCOS has a very fast T90 response time was set 100 ms for liquid. When the heart rate of 40%~60% oxygen mechanical ventilated living goat was ~110 bpm, the PaO2 of left and right carotid artery showed a same wave-sizeup and down following with the inspiration and expiration of ventilator, with a range of up to 15 mmHg. There weresignificant noises of PaO2 change recorded in the left femoral artery. The lung-carotid artery time delay is 1.5~1.7 s after inhalation and exhalation, PaO2 at both left and right carotid arteries starts toincrease and decrease. After two-three heartbeats after the start of lung ventilation, thealternate up-down wave-form information of the arterialized pulmonary vein blood after pulmonary capillaries waspumpedby left ventricle to the position of peripheral chemoreceptors,thus realizing the whole cycle of inhalation and exhalation. It alternately interrupted inhalation, i.e. switching inhalation to exhalation, and then interrupted exhalation,i.e. switching exhalation to inhalation. Conclusion: The ultra-fast reactive implantableoxygen sensor and its measuring system can measure the physiological waveform changes of PaO2 in living animals, which can provide experimental evidence for explaining the mechanism of switching of inspiration-expiration in HIPM.

Advantages of 3PLs as healthcare supply chain orchestrators.

Given the expansion of the COVID-19 cases and the average infection rate globally, constructing a robust healthcare supply chain system for the crisis is highly crucial. The third-party logistics providers (3PLs), who can match the market demand with reliable manufacturers worldwide, have emerged as orchestrators. In addition to the basic transportation and storage services, some 3PLs can also provide procurement assistance to relatively small retailers. To illustrate the value of the above-mentioned business model, we build a game-theoretic model to capture participants' optimal strategy in a healthcare supply chain consisting of a manufacturer, a 3PL provider, and a retailer. We also investigate the conditions where the performance in this business model outperforms the traditional model. It is concluded that the 3PL's positive effect appears when the decentralized supply chain is characterized by high logistics outsourcing costs and high-level price sensitivity. We further design an incentive mechanism that can coordinate the supply chain. Finally, a series of numerical experiments are carried out to demonstrate the effectiveness of our model.

Association of preoperative frailty with postoperative delirium after elective brain tumor resection: Retrospective analysis of a prospective cohort.

BACKGROUND: Preoperative frailty is associated with poor outcomes in major surgery. Postoperative delirium is common after neurosurgery. To date, the association of preoperative frailty with postoperative delirium after neurosurgery has not been established. We aimed to determine the association between preoperative frailty and postoperative delirium in patients undergoing elective brain tumor resection. METHODS: We retrospectively analyzed the data of a prospective cohort, consecutively enrolling adult patients admitted to the intensive care unit after elective craniotomy for brain tumor resection under general anesthesia in a tertiary hospital in China from March 1, 2017 to February 2, 2018. Preoperative frailty was evaluated using the modified frailty index. The primary outcome was postoperative delirium, assessed using the Confusion Assessment Method for the Intensive Care Unit. Univariate and multivariable regression analyses were performed to examine the association. RESULTS: 659 patients met inclusion criteria for our analysis. There were 398 (60.4%) non-frail (modified frailty index = 0), 237 (36.0%) pre-frail (modified frailty index = 1-2), and 24 (3.6%) frail (modified frailty index ≥ 3) patients. Of these, 124 (18.8%) developed postoperative delirium. In adjusted analyses, frailty was independently associated with postoperative delirium (odds ratio 1.7, 95% confidence interval 1.0-2.7, P = .032). Frail patients had longer length of hospital stay and higher total costs than non-frail patients. CONCLUSION: Preoperative frailty is associated with postoperative delirium, length of hospital stay, and total costs in patients undergoing elective brain tumor resection. Preoperative frailty assessment and appropriate management strategies should be involved in the perioperative management of postoperative delirium.

Distinct outcomes of labetalol exposed infants: case reports and systematic review.

BACKGROUND: The adverse effects of long-term maternal exposure of labetalol on neonates have been recognized clinically. But there are few systematic studies on their clinical demonstrations and potential mechanisms. METHODS: A death case of an infant with long-term maternal labetalol exposure was reported and compared with two case reports from the literature. A systematic literature review was carried out followed by a retrospective analysis on neonatal labetalol withdrawal effects. RESULTS: It was discovered that labetalol withdrawal effects initially cause various degrees of hypotension, hypoglycemia, and bradycardia among exposed neonates. Some life-threatening cases can also occur within 1 week after birth. Long-term maternal exposure of labetalol, preterm infants with birth asphyxia, acidosis, hypoalbuminemia, and cardiac defects are their primary features. Possible mechanisms were concluded as labetalol-induced effects on the vascular and sympathetic nervous system as well as tissue oxygen extraction. CONCLUSIONS: Neonatal labetalol withdrawal effects include early-onset and late-onset demonstrations, the latter can be life-threatening. A possible mechanism is multiple factors induced imbalance of sympathetic homeostasis increases neonatal vulnerability to common stresses. Long-term exposed preterm infants complicated with asphyxia, acidosis, hypoalbuminemia and cardiac defects, should be provided with intense care during the first week after birth. Further work is necessary to enrich this hypothesis.

90 days impacts of remote ischemic preconditioning on patients undergoing open total aortic arch replacement: a post-hoc analysis of previous trial.

BACKGROUND: In the previous randomized controlled trial by our research group, we evaluated the effect of remote ischemic preconditioning (RIPC) in 130 patients (65 per arm) on acute kidney injury (AKI) within 7 days of open total aortic arch replacement. Significantly fewer RIPC-treated patients than sham-treated patients developed postoperative AKI, and, epically, RIPC significantly reduced serious AKI (stage II-III). However, the long-term effect of RIPC in patients undergoing open total aortic arch replacement is unclear. METHODS: This study was a post-hoc analysis. We aimed to assess the roles of RIPC in major adverse kidney events (MAKE), defined as consisting persistent renal dysfunction, renal replacement therapy and mortality, within 90 days after surgery in patients receiving open total aortic arch replacement. RESULTS: In this 90-day follow-up study, data were available for all study participants. We found that RIPC failed to improve the presence of MAKE within 90 days after surgery (RIPC: 7 of 65[10.8%]) vs sham: 15 of 65[23.1%]; P = 0.061). In those patients who developed AKI after surgery, we found that the rate of MAKE within 90 days after surgery differed between the RIPC group and the sham group (RIPC: 4 of 36[11.2%]; sham: 14 of 48[29.2%]; P = 0.046). CONCLUSIONS: At 90 days after open total aortic arch replacement, we failed to find a difference between the renoprotective effects of RIPC and sham treatment. The effectiveness or ineffectiveness of RIPC should be further investigated in a large randomized sham-controlled trial. TRIAL REGISTRATION: This study was approved by the Ethics Committee of Fuwai Hospital (No. 2016-835) and our previous study was registered at clinicaltrials.gov before patient enrollment ( NCT03141385 ; principal investigator: G.W.; date of registration: March 5, 2017).

Using Machine Learning to Predict Acute Kidney Injury After Aortic Arch Surgery.

OBJECTIVES: Machine learning models were compared with traditional logistic regression with regard to predicting kidney outcomes after aortic arch surgery. DESIGN: Retrospective review. SETTING: Single quaternary care center, Fuwai Hospital, Beijing, China. PARTICIPANTS: The study comprised 897 consecutive patients who underwent aortic arch surgery from January 2013 to May 2017. Three machine learning methods were compared with logistic regression with regard to the prediction of acute kidney injury (AKI) after aortic arch surgery. Perioperative characteristics, including patients' baseline medical condition and intraoperative data, were analyzed. The performance of the models was assessed using the area under the receiver operating characteristic curve. MEASUREMENTS AND MAIN RESULTS: The primary endpoint, postoperative AKI, was defined using the Kidney Disease: Improving Global Outcomes criteria. During the first 7 postoperative days, AKI was observed in 652 patients (72.6%), and stage 2 or 3 AKI developed in 283 patients (31.5%). Gradient boosting had the best discriminative ability for the prediction of all stages of AKI in both the binary classification and the multiclass classification (area under the receiver operating characteristic curve 0.8 and 0.71, respectively) compared with logistic regression, support vector machine, and random forest methods. CONCLUSION: Machine learning methods were found to predict AKI after aortic arch surgery significantly better than traditional logistic regression.

Postoperative liver dysfunction after total arch replacement combined with frozen elephant trunk implantation: incidence, risk factors and outcomes.

OBJECTIVES: The authors aimed to clarify the incidence and risk factors of postoperative liver dysfunction (PLD) in patients undergoing total arch replacement combined with frozen elephant trunk implantation and to determine the association of PLD with short-term outcomes. METHODS: Data from 672 adult patients undergoing total arch replacement with frozen elephant trunk from January 2013 until December 2016 at Fuwai Hospital were analysed retrospectively. A multivariable logistic regression model was used to identify the risk factors for PLD. RESULTS: The overall incidence of PLD was 27.5%, which was associated with higher in-hospital mortality (PLD 4.9% vs No PLD 0.8%, P = 0.002) and 30-day mortality (PLD 9.2% vs No PLD 2.5%, P < 0.001) and a higher incidence of major adverse events (PLD 54.6% vs No PLD 23.4%, P < 0.001). In the multivariable analysis, preoperative hypotension [odds ratio (OR) 1.97, 95% confidence interval (CI) 1.14-3.41; P = 0.02), coronary artery disease (OR 2.64, 95% CI 1.17-5.96; P = 0.02), prolonged cardiopulmonary bypass duration (OR 1.01, 95% CI 1.00-1.01; P < 0.001), increased preoperative alanine transferase (OR 1.01, 95% CI 1.00-1.01; P < 0.001), preoperative platelet count <100 × 109/l (OR 3.99, 95% CI 1.74-9.14; P = 0.001) and increased intraoperative erythrocyte transfusion (OR 1.07, 95% CI 1.01-1.12; P = 0.02) were identified as independent risk factors for PLD. CONCLUSIONS: PLD was associated with increased mortality and morbidity. Among the independent risk factors for PLD, cardiopulmonary bypass duration and erythrocyte transfusion could be modifiable. A skilled surgical team and an ideal blood protection strategy may be helpful to protect liver function.

Single-Stage Hybrid Aortic Arch Repair is Associated With a Lower Incidence of Postoperative Acute Kidney Injury Than Conventional Aortic Surgery.

OBJECTIVES: The authors compared the renal outcomes of single-stage hybrid aortic arch repair without deep hypothermic circulatory arrest versus conventional total arch replacement in management of thoracic aortic diseases. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review from January 2013 to December 2016 in Fuwai Hospital of 757 consecutive patients who underwent aortic arch repair: conventional total arch replacement (CTAR, 651), and hybrid arch repair (HAR, 106), with propensity matching (95 pairs). MEASUREMENTS AND MAIN RESULTS: The primary end-point was postoperative acute kidney injury (AKI) defined using the Kidney Disease Improving Global Outcome criteria. The secondary end-point was short-term outcomes such as in-hospital mortality and paraplegia determined by the Society of Thoracic Surgeons. The patients in the HAR group were older (60.20 ± 9.95 v 46.43 ± 10.79, p < 0.0001) and exhibited a greater rate of diabetes (11.3% v 2.0%, p = 0.0004), hyperlipidemia (47.2% v 25.4%, p < 0.0001), and coronary artery disease (13.2% v 4.3%, p < 0.0001) than those in the CTAR group. Following propensity score matching of 95 matched pairs, the difference in preoperative risk diminished. The HAR group led to a shorter cardiopulmonary bypass time (133.33 ± 41.47 v 179.62 ± 40.79, p < 0.0001) and avoided circulatory arrest. The incidence of postoperative AKI between HAR and CTAR groups was significantly different (before match: 75.5% v 59.45%, p = 0.0046; after match: 78.9% v 57.9%, p = 0.0008). CONCLUSION: In the management of thoracic aortic diseases, HAR is associated with a significantly lower incidence of postoperative AKI, and showed equivalent short-term outcomes despite the older age compared with the CTAR group.