Evaluation of phase-adjusted interventions for COVID-19 using an improved SEIR model.

A local COVID-19 outbreak with two community clusters occurred in a large industrial city, Shaoxing, China, in December 2021 after serial interventions were imposed. We aimed to understand the reason by analysing the characteristics of the outbreak and evaluating the effects of phase-adjusted interventions. Publicly available data from 7 December 2021 to 25 January 2022 were collected to analyse the epidemiological characteristics of this outbreak. The incubation period was estimated using Hamiltonian Monte Carlo method. A well-fitted extended susceptible-exposed-infectious-recovered model was used to simulate the impact of different interventions under various combination of scenarios. There were 387 SARS-CoV-2-infected cases identified, and 8.3% of them were initially diagnosed as asymptomatic cases. The estimated incubation period was 5.4 (95% CI 5.2-5.7) days for all patients. Strengthened measures of comprehensive quarantine based on tracing led to less infections and a shorter duration of epidemic. With a same period of incubation, comprehensive quarantine was more effective in containing the transmission than other interventions. Our findings reveal an important role of tracing and comprehensive quarantine in blocking community spread when a cluster occurred. Regions with tense resources can adopt home quarantine as a relatively affordable and low-impact intervention measure compared with centralized quarantine.

Effects of dexmedetomidine at different dosages on perioperative haemodynamics and postoperative recovery quality in elderly patients undergoing hip replacement surgery under general anaesthesia: a randomized controlled trial.

BACKGROUND: Dexmedetomidine could provide some advantages to prevent postoperative complications in elderly patients undergoing under general anaesthesia. However, dexmedetomidine inhibits haemodynamics to some extent due to its sympathetic inhibition. OBJECTIVE: To evaluate the effects of different doses of dexmedetomidine on haemodynamics during surgery and recovery after general anaesthesia in elderly patients undergoing hip replacement. METHODS: This was a prospective randomized double-blind controlled clinical trial. Eligible patients were randomly allocated into comparative groups (normal saline (NS) and midazolam (MD), n = 30) and dexmedetomidine groups at different doses (D0.25/D0.5/D0.75, n = 30). In the D0.25/D0.5/D0.75 groups, dexmedetomidine was administered at different initial loading doses (0.25/0.5/0.75 µg/kg for 15 min) following 0.5 µg/kg/h continuous infusion until the end of the operation. In the MD group, patients were administered 0.03 mg/kg midazolam at the beginning of anaesthesia induction. RESULTS: Compared to the MD and NS groups, there were significant decreases in MAP in the D0.5 and D0.75 groups at many time points, such as skin incision, end of operation, and from extubation until 30 min after extubation (P < 0.05); there were also significant decreases in HR in the D0.5 and D0.75 groups at time points including anaesthesia induction, end of operation, and from extubation to 2 h after operation (P < 0.05). In the D0.25 group, there were few differences in the changes in MAP and HR compared to the MD and NS groups during the entire perioperative period (P > 0.05). Moreover, the percentage of patients whose MAP and HR decreased > 20% of baseline was higher in the D0.75 and D0.5 groups than that in all other groups. Compared to the NS group, from the beginning to the end of the operation, the 95% confidence interval (CI) of RR for MAP below > 20% of baseline in the D0.5 and D0.75 groups was greater than 1. In particular, the CI of the RR in the D0.75 group was greater than 1 until the patient awoke from general anaesthesia (P < 0.05). In addition, the CI of the RR for HR below > 20% of baseline in the D0.5 group was greater than 1 compared to the NS group at the time of induction and extubation (P < 0.05). There was no significant difference in the possibility of developing hypotension or bradycardia in the MD or D0.25 groups compared to the NS group (P > 0.05). The recovery quality of patients during the post-anaesthesia period was also observed. No differences were observed among all the groups in the time to awakening or extubation after general anaesthesia (P > 0.05). According to the Riker Sedation-agitated Scale, dexmedetomidine significantly alleviated emergency agitation or delirium compared to NS (P < 0.05). In addition, the scores in the D0.5 and D0.75 groups were lower than those in the D0.25 group (P < 0.05). CONCLUSION: Dexmedetomidine could alleviate the agitation of elderly patients undergoing hip replacement after intravenous general anaesthesia combined with inhaled sevoflurane without delayed recovery. However, it is necessary to be vigilant about the haemodynamic inhibition of the drug at high dosages throughout the perioperative period. Dexmedetomidine 0.25-0.5 µg/kg as the initial loading dose followed by 0.5 µg/kg/h continuous infusion might provide comfortable recovery after general anaesthesia with slight haemodynamic inhibition. TRAIL REGISTRATION: ClinicalTrial.gov, No. NCT05567523. Registered 05 October 2022, https://clinicaltrials.gov/ct2/show/NCT05567523?term=NCT05567523&draw=2&rank=1 .

[D-Ala2, D-Leu5] Enkephalin Inhibits TLR4/NF-κB Signaling Pathway and Protects Rat Brains against Focal Ischemia-Reperfusion Injury.

BACKGROUND: Cerebral ischemia-reperfusion (I/R) injury is the main cause of acute brain injury, which is a life-threatening disease due to the lack of effective treatments. [D-Ala2, D-Leu5] enkephalin (DADLE) is a synthetic delta-opioid receptor agonist that is reported to confer neuroprotective effect; however, the underlying mechanism is still being explored. The purpose of the present study is to determine whether DADLE administrated intracerebroventricularly could attenuate the cerebral I/R injury, to determine if this is through inhibiting the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling pathway and therefore inhibiting neuroinflammation in an ischemic stroke model. METHODS: Rats were subjected to 120 minutes of ischemia by transient middle cerebral artery occlusion (MCAO). At 45 minutes after ischemia, DADLE or control vehicle (artificial cerebrospinal fluid, ACSF) was given to the rats intracerebroventricularly. Neurological deficit, cerebral infarct volume, and histopathological changes were assessed at 24 hours after reperfusion. Brain inflammation was assessed by measuring tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the ischemic penumbra by ELISA. The expression of TLR4 was determined by immunohistochemistry staining and western blotting. The expression of NF-κB was investigated by western blotting. RESULTS: Compared with the vehicle-treatment (ACSF), DADEL improved neurological deficit (9.6 ± 2.1 versus 13.8 ± 1.9), reduced cerebral infarct volume (18.74 ± 3.30% versus 10.57 ± 2.50%), and increased the number of normal neurons (29.72 ± 8.53% versus 51.37 ± 9.18%) after cerebral I/R injury in rats (all P < 0.05). Expressions of inflammatory molecules including TNF-α and IL-6 were highly expressed in the vehicle-treated rats, whereas treatment with DADLE downregulated these expressions (P < 0.05). Additionally, cerebral I/R injury significantly increased the TLR4 and NF-κB expression in vehicle-control group, which was markedly inhibited by DADLE (P < 0.05). CONCLUSIONS: DADLE, administrated intracerebroventricularly at 45 minutes after cerebral ischemia, significantly ameliorated I/R-induced brain damage in rats. This kind of neuroprotective effect appears to be related to the downregulation of TLR4-mediated inflammatory responses.

Effects of D­Ala2, D­Leu5­Enkephalin pre­ and post­conditioning in a rabbit model of spinal cord ischemia and reperfusion injury.

It has recently been revealed that during the aorta­clamped period, D­Ala2, D­Leu5­Enkephalin (DADLE) infusion can protect the spinal cord against ischemia and reperfusion (I/R) injury. However, the protective effects of DADLE administration prior to ischemia or at the time of early reperfusion have not yet been investigated. Drug pre­ or post­conditioning can serve as a more valuable clinical strategy. Therefore, the present study was designed to investigate the neuroprotective effect of DADLE infusion at different time intervals in order to determine the optimum time point for ischemic spinal cord protection. A total of 40 New Zealand white rabbits were randomly divided into 5 groups: Sham­operated (Sham), normal saline pre­conditioning (NS), DADLE per­conditioning (Dper), DADLE pre­conditioning (Dpre) and DADLE post­conditioning (Dpost). All animals were subjected to spinal cord ischemia for 30 min followed by 48 h reperfusion. Hind limb motor functions were assessed according to the Tarlov criterion when the animals regained consciousness, 6, 24 and 48 h after reperfusion. Histological analysis and the number of viable α­motor neurons were also used to assess the extent of spinal cord injury. Compared with the NS group, the Tarlov scores and the number of normal neurons were significantly higher in the Dper group (P<0.05), which were consistent with the results of a previous study. In addition, the paraplegia rate and loss of normal motor neurons were lower in the DADLE per­ and post­conditioning groups compared with the DADLE pre­conditioning; however, these were not statistically significant. DADLE 0.05 mg/kg administration at three time points all mitigated normal motor neuron injury in the anterior horn and decreased the paraplegia rates in rabbits. The therapeutic benefits appeared best in the post­conditioning group with DADLE, and worst in the pre­conditioning group.

Hypoxia-Activated and Indomethacin-Mediated Theranostic Prodrug Releasing Drug On-Demand for Tumor Imaging and Therapy.

A smart theranostic prodrug IMC-FDU-TZBC-NO2, releasing active drug on-demand based on hypoxia-activated and indomethacin-mediated, for solid tumor imaging and efficient therapy was designed. This prodrug was constructed by conjugating chemotherapy drug 5-fluoro-2-deoxyuridine (FDU), targeting moiety indomethacin (IMC), and the hypoxic trigger 4-nitrobenzyl group to a fluorescent dye precursor, which was mediated by IMC and activated by NTR under hypoxic conditions. The fluorescent dye IMC-TZBCM was generated and FDU was released at the same time in tumor cells. The rates and amounts of FDU release and IMC-TZBCM generation were regulated by hypoxia status, and increased with increasing degree of hypoxia. Nevertheless, it is "locked" in normal cells. It combined the advantages of tumor targeting, diagnosis, and chemotherapy functions, showed excellent targeting ability to cancer cells, excellent stability in physiological conditions, high cellular uptake efficiency, and on-demand drug release behavior. The in vitro and in vivo assays demonstrated that IMC-FDU-TZBC-NO2 exhibits enhanced anticancer potency and low side effects. The novel targeted theranostic prodrug activated by hypoxia shows a great potential in cancer therapy.

Efficacy of short-term intensive treatment with insulin pump to improve islet ß-cell function in newly diagnosed type 2 diabetes via inhibition of oxidative stress.

The present study (Chinese Trial Registry GTB7027) assessed the effects of short-term intensive treatment with insulin pump on islet cell function in patients with newly diagnosed type 2 diabetes and the possible mechanism. A total of 100 patients newly diagnosed with type 2 diabetes and hospitalized between January 2016 and December 2017 were divided into a control and an experimental group (n=50 in each group). The subjects of the control group were administered multiple insulin injections for intensive treatment, while the experimental group received short-term intensive treatment with an insulin pump. Analysis of blood parameters, including lipids and glucose, as well as islet ß-cell function were performed. The level of reactive oxygen species (ROS) in the peripheral blood mononuclear cells (PBMCs) from the patients was also measured. Oxidative stress indicators, including serum malondialdehyde (MDA) and superoxide dismutase (SOD), were also examined to explore the possible mechanism. The mRNA expression of heme oxygenase 1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in PBMCs were analyzed by reverse transcription-quantitative PCR. The results indicated that the blood lipid levels were significantly improved in the two groups at two weeks, while the experimental group had significantly lower levels of total cholesterol and triglyceride, as well as low- and high-density lipoprotein cholesterol. The function of islet ß-cells was significantly improved in the two groups. The insulin secretion index [homeostasis model assessment (HOMA) of ß-cell function] in the experimental group was higher, while the insulin resistance (IR) index (HOMA of IR) was significantly lower than that in the control group. The serum MDA level in the experimental group was significantly lower and the SOD level was significantly higher compared with that in the control group. Following treatment, the level of ROS in diabetic PBMCs was significantly reduced, and the transcription level of HO-1 and Nrf2 were also significantly reduced (P<0.05). These results demonstrated that short-term intensive treatment with an insulin pump significantly improved lipid and blood glucose metabolism to protect islet function as well as significantly reducing the level of oxidative stress in patients with newly diagnosed type 2 diabetes.

Hypoxia-Activated Anticancer Prodrug for Bioimaging, Tracking Drug Release, and Anticancer Application.

A novel anticancer theranostic prodrug, FDU-DB-NO2, specifically activated by hypoxia for selective two-photon imaging hypoxia status, real-time tracking drug release, and solid tumor therapy was designed. The devised prodrug consists of an anticancer drug floxuridine (FDU), a fluorescence dye precursor 4'-(diethylamino)-1,1'-biphenyl-2-carboxylate (DB), and a hypoxic trigger 4-nitrobenzyl group. In normal cells, FDU-DB-NO2 is "locked". Whereas in tumor cells, the prodrug is "unlocked" by hypoxia and results in fluorescent dye 7-(diethylamino)coumarin (CM) generation along with FDU release. The amounts and rates of CM formation and FDU release were controlled by hypoxic status and increased with the decreasing of the O2 concentration. The hypoxic status, distribution of oxygen, and amount of FDU release in tumor cells, spheroids, and tumor tissue could be visualized by fluorescence. FDU-DB-NO2 showed high cytotoxicity against hypoxic MCF-7 and MCG-803 cell lines and no cytotoxicity against normoxic BRL-3A cells and exhibited effective inhibition on tumor growth of MCF-7-cell-inoculated xenograft nude mice. This strategy may provide a promising platform for selective two-photon imaging hypoxia status, real-time tracking drug release, and personalized solid tumor treatment.

Antioxidative and Antiapoptotic Effects of Delta-Opioid Peptide [D-Ala2, D-Leu5] Enkephalin on Spinal Cord Ischemia-Reperfusion Injury in Rabbits.

Background: In our previous study, we found that regional administration of delta-opioid peptide [D-Ala2, D-Leu5] enkephalin (DADLE) could provide dose-dependent protection on spinal cord ischemia-reperfusion (I/R) injury in rabbits. However, the relative protective molecular mechanisms underlying this neuroprotection remain unclear. The purpose of this study was to investigate whether DADLE provided the protection in spinal cord I/R injury through its antioxidant property by decreasing malondialdehyde (MDA) and nitric oxide (NO) levels and increasing glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) levels and through its antiapoptotic capacity by inhibiting caspase-3 and p53 expression. Methods: The rabbits were divided into three groups. The animals in Group NS and Group DADLE were administered with normal saline (NS) or DADLE via aorta during 30 min of ischemia respectively, while the one in Group Sham received no intervention. During the period of reperfusion, the rabbit's blood samples were collected for enzyme-linked immunoabsorbent assay (ELISA) examinations of MDA, NO, GSH-Px and SOD. At 48 h after reperfusion, the lumbar spinal cords were harvested for immunohistochemical, real-time polymerase chain reaction (PCR) and western blot studies to detect the caspase-3 and p53 expressions. Results: The activities of serum MDA and NO showed significant reductions in the DADLE group as compared with the control group. By contrast, the levels of serum GSH-Px and SOD were significantly higher in the DADLE group than those in the NS group. In addition, caspase-3 and p53 expression were significantly increased in the NS group, while DADLE mitigated these changes. Conclusions: The protective effects of DADLE at the dosage of 0.05 mg/kg may be related to its antioxidant and antiapoptosis properties in the rabbit model of spinal cord I/R injury.

Protective effect of delta opioid receptor agonist (D-Ala2, D-Leu5) enkephalin on permanent focal cerebral ischemia in rats.

To investigate the effect of delta opioid receptor agonist (D-Ala, D-Leu) enkephalin (DADLE) on the permanent focal cerebral ischemia in rats. Thirty four male Sprague-Dawley rats were assigned randomly into three groups: sham group (group Sham, n=10), artificial cerebrospinal fluid group (group ACSF, n=12), and DADLE group (group DADLE, n=12). Permanent middle cerebral artery occlusion was performed to induce permanent focal cerebral ischemia in rats. Then, the animals in group DADLE and group ACSF were treated with DADLE or ACSF by an intracerebroventricular injection at 45 min after ischemia. Neurologic deficit scores were assessed according to the Garcia criterion at 24 h after ischemia. Infarct volume was determined using the 2,3,5-triphenyltetrazolium chloride staining method. The histological analysis was used to evaluate the extent of cerebral injury. Compared with the control group, the Garcia scores were significantly higher (P=0.000) and the infarct volumes (P=0.018) were significantly smaller in the DADLE treatment group at 24 h after ischemia. These neurologic changes were closely correlated with the outcome of the infarct volumes. In addition, the histological examination showed more intact neurons in rats treated with DADLE than those treated with ACSF at 24 h after ischemia (P=0.000). DADLE by intracerebroventricular administration at 45 min after ischemia can improve neurologic outcome and mitigate cortical neuronal injury induced by permanent focal cerebral ischemia in rats.

Dose-dependent neuroprotection of delta-opioid peptide [D-Ala(2), D-Leu(5)] enkephalin on spinal cord ischemia-reperfusion injury by regional perfusion into the abdominal aorta in rabbits.

OBJECTIVE: In our prior study, we showed that delta-opioid peptide [D-Ala(2), D-Leu(5)] enkephalin (DADLE), by regional perfusion into the abdominal aorta, could protect the spinal cord against ischemia-reperfusion (I/R) injury caused by aortic occlusion. However, the relative dose-response effects of DADLE still remain unclear. This study investigated whether DADLE has a dose-dependent efficiency on spinal cord I/R injury. METHODS: New Zealand White rabbits were randomly divided into one of six groups: normal saline (NS; n = 8), DADLE (D) groups D0.0005 (n = 8), D0.005 (n = 8), D0.05 (n = 8), and D0.5 mg/kg (n = 8), and a sham group (n = 6). In the NS and DADLE groups, spinal cord ischemia was induced by infrarenal aortic occlusion for 30 minutes. During the occlusion, the same volume of NS or DADLE at the indicated doses was infused continuously through a catheter to the distally clamped abdominal aorta. Heart rate, blood pressure, and core temperature were monitored continuously to evaluate the potential adverse effects of DADLE. Neurologic behavioral function was assessed with the Tarlov scale system at 1, 6, 24, 48, and 72 hours after reperfusion. Neuronal injury evaluation in the ventral horn of the gray matter was evaluated by counting the normal motor neurons at 72 hours after reperfusion. RESULTS: The therapeutic benefits increased at the doses of DADLE from 0.0005 to 0.05 mg/kg and decreased at 0.5 mg/kg, whereas the hemodynamic parameter was suppressed temporarily at the dose of 0.5 mg/kg. CONCLUSIONS: These data revealed that regional administration of DADLE through the abdominal aorta provided dose-dependent protection on spinal cord I/R in rabbits.

Protective effect of delta opioid agonist [D-Ala2, D-Leu5] enkephalin on spinal cord ischemia reperfusion injury by regional perfusion into abdominal aorta in rabbits.

[D-Ala(2), D-Leu(5)] enkephalin (DADLE) has been reported to exhibit protective effects against hypoxic or ischemic induced brain insult. However its efficacy on the spinal cord ischemia-reperfusion injury remains unclear. Here we investigate whether DADLE could attenuate ischemia and reperfusion induced neural injury in the rabbit spinal cord. New Zealand white rabbits were subjected to spinal cord ischemia by infrarenal aortic occlusion for 30 min. In the period of spinal cord ischemia, DADLE 0.5 mg/kg or NS were infused continuously into the distal clamped abdominal aorta. The heart rate, blood pressure, and core temperature were monitored continuously during the whole experimental procedure. Then the neurological behavioral function was assessed with Tarlov scale system at 1h, 6h, 24h, 48 h after reperfusion, and neuronal injury evaluation in the ventral horn of gray matter was measured by counting the normal motor neurons at 48 h after reperfusion. Comparing with the control group, the Tarlov scores were significantly higher and the incidences of paraplegia were significantly lower in the DADLE group at four time-point recorded. In addition, the normal neurons numbers in the DADLE group were significant more than those in the control group at 48 h after reperfusion. These results suggested that DADLE infused into the abdominal aorta during ischemia period could attenuate behavioral retardation and the loss of normal motor neuron induced by ischemia-reperfusion in rabbits.