Thermoresponsive Polymeric Hydromorphone Prodrug Provides Sustained Local Analgesia without Apparent Adverse Effects.

The extensive use of opioids for chronic pain management has contributed significantly to the current opioid epidemic. While many alternative nonopioid analgesics are available, opioids remain the most potent analgesics for moderate to severe pain management. In addition to the implementation of multimodal analgesia, there is a pressing need for the development of more effective and safer opioids. In this study, we developed a thermoresponsive N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based hydromorphone (HMP) prodrug (ProGel-HMP, HMP content = 16.2 wt %, in base form). The aqueous solution of ProGel-HMP was free-flowing at 4 °C but became a hydrogel when the temperature was raised to ≥37 °C, allowing sustained local retention when administered in vivo. When tested in the destabilization of the medial meniscus (DMM) mouse model of osteoarthritis (OA), ProGel-HMP was retained after intra-articular injection in the OA knee joint for at least 2 weeks postinjection, with low extra-articular distribution. ProGel-HMP was not detected in the central nervous system (CNS). A single dose of ProGel-HMP produced rapid and sustained joint pain resolution for greater than 14 days when compared to saline and dose-equivalent HMP controls, likely mediated through peripheral µ-opioid receptors in the knee joint. Systemic analgesia effect was absent in the DMM mice treated with ProGel-HMP, as evident in the lack of difference in tail flick response between the ProGel-HMP-treated mice and the controls (i.e., Healthy, Saline, and Sham). Repeated dosing of ProGel-HMP did not induce tolerance. Collectively, these data support the further development of ProGel-HMP as a potent, safe, long-acting and nonaddictive analgesic for better clinical pain management.

Expert consensus on perioperative integrated skincare for noninvasive energy-based device aesthetic procedures in clinical practice in China.

BACKGROUND: Noninvasive energy-based device (NI-EBD) aesthetic procedures has recently gained widespread usage for treating various skin conditions, enhancing skin texture and performing rejuvenation-related procedures. However, practically all NI-EBD procedures result in variable degrees of damage to the skin barrier, inducing pathological and physiological processes such as oxidative stress and inflammation, and only a small percentage of individuals possess the innate ability to restore it. OBJECTIVE: To introduce the concept of integrated skincare and establish standardized operational procedures for perioperative integrated skincare, and furnish a theoretical basis for clinical diagnosis and treatment performed by professional medical aestheticians. METHODS: The author leveraged domestic and international guidelines, clinical practice expertise and evidence-based research, adapting them to suit the specific circumstances in China. RESULTS: The consensus were provided four parts, including concept and essence of integrated skincare, integrated skincare significance during the perioperative phase of NI-EBD procedures, active ingredients and functions of effective skincare products, standardized perioperative skincare procedure for NI-EBD procedures and precautions. For the standardized perioperative skincare procedure, four recommendations were listed according to different stages during NI-EBD procedures. CONCLUSION: These recommendations create the 'Expert Consensus on Perioperative Integrated Skincare for Noninvasive Energy-Based Device Aesthetic Procedures in Clinical Practice in China'.

Single dose thermoresponsive dexamethasone prodrug completely mitigates joint pain for 15 weeks in a murine model of osteoarthritis.

In this study, we aimed to assess the analgesic efficacy of a thermoresponsive polymeric dexamethasone (Dex) prodrug (ProGel-Dex) in a mouse model of osteoarthritis (OA). At 12 weeks post model establishment, the OA mice received a single intra-articular (IA) injection of ProGel-Dex, dose-equivalent Dex, or Saline. Comparing to Saline and Dex controls, ProGel-Dex provided complete and sustained pain relief for >15 weeks according to incapacitance tests. In vivo optical imaging confirmed the continuous presence of ProGel-Dex in joints for 15 weeks post-injection. According to micro-CT analysis, ProGel-Dex treated mice had significantly lower subchondral bone thickness and medial meniscus bone volume than Dex and Saline controls. Except for a transient delay of body weight increase and slightly lower endpoint liver and spleen weights, no other adverse effect was observed after ProGel-Dex treatment. These findings support ProGel-Dex's potential as a potent and safe analgesic candidate for management of OA pain.

Epstein-Barr virus variation in people living with human immunodeficiency virus in southeastern China.

BACKGROUND: Patients infected with HIV are at high risk of developing Epstein-Barr Virus (EBV)-related diseases. The genotype and viral biological behavior of EBV infection in patients with human immunodeficiency virus-1 (HIV) in China remain unclear. This study analyzed the characteristics of EBV in patients infected with HIV in southeastern China. METHODS: A total of 162 HIV-infected patients and 52 patients without HIV were enrolled in this study. EBV viral load in blood was determined by fluorescence quantitative PCR. EBV typing was performed using saliva according to polymorphisms in the EBNA3C region. EBV LMP-1 carboxy terminus (C-ter) was sequenced, and compared with the epidemic strains in the world. RESULTS: Among HIV infected patients, the EBV strain variant was mainly EBV-1, while EBV-2 had a higher viral load than EBV-1 (P = 0.001) and EBV-1/2 (P = 0.002). HIV infected patients had higher active virus replication. The EBV LMP-1 variants were mainly the China1 variant. HIV-infected patients had different nucleic acid positions of 30-bp deletion (del30) and had a higher incidence of high 33-bp tandem repeats (rep33) copies than non-HIV-infected patients. There was a difference in the mutations of EBV LMP-1 C-ter del30 and ins15 between HIV infected patients and the control group (P < 0.001). CONCLUSION: In southeastern China, EBV in HIV-infected patients had higher active virus replication; EBV infection was mainly EBV-1, and EBV-2 infection has higher EBV virus load; hotspot mutations of LMP-1 C-ter were different between HIV-infected patients and non-HIV-infected patients. TRIAL REGISTRATION: This study was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University School of Medicine (Approval No. 2018764), and registered in Chinese Clinical Trial Registry on 3 June 2019 (ChiCTR, ChiCTR1900023600, http://www.chictr.org.cn/usercenter.aspx ).

The Development of Thermoresponsive Polymeric Simvastatin Prodrug for the Treatment of Experimental Periodontitis in Rats.

Periodontitis (PD) is a severe inflammatory gum pathology that damages the periodontal soft tissue and bone. It is highly prevalent in the US, affecting more than 47% of adults. Besides routine scaling and root planing, there are few effective treatments for PD. Developed as an effective treatment for hyperlipidemia, simvastatin (SIM) is also known for its well-established anti-inflammatory and osteogenic properties, suggesting its potential utility in treating PD. Its clinical translation, however, has been impeded by its poor water-solubility, lack of osteotropicity, and side effects (e.g., hepatoxicity) associated with systemic exposure. To address these challenges, an N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based thermoresponsive polymeric prodrug of SIM (ProGel-SIM) was developed as a local therapy for PD. Its aqueous solution is free-flowing at 4 °C and transitions into a hydrogel at ∼30 °C, allowing for easy local application and retention. After a thorough characterization of its physicochemical properties, ProGel-SIM was administered weekly into the periodontal pocket of an experimental rat model of PD. At 3 weeks post initiation of the treatment, the animals were euthanized with palate isolated for µ-CT and histological analyses. When compared to dose equivalent simvastatin acid (SMA, active form of SIM) treatment, the rats in the ProGel-SIM treated group showed significantly higher periodontal bone volume (0.34 mm3 vs 0.20 mm3, P = 0.0161) and less neutrophil (PMN) infiltration (P < 0.0001) and IL-1ß secretion (P = 0.0036). No measurable side effect was observed. Collectively, these results suggest that ProGel-SIM may be developed as a promising drug candidate for the effective clinical treatment of PD.

Reproduction Numbers of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants: A Systematic Review and Meta-analysis.

The coronavirus disease 2019 (COVID-19) pandemic continues to pose substantial risks to public health, worsened by the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that may have a higher transmissibility and reduce vaccine effectiveness. We conducted a systematic review and meta-analysis on reproduction numbers of SARS-CoV-2 variants and provided pooled estimates for each variant.

Serial Intervals and Case Isolation Delays for Coronavirus Disease 2019: A Systematic Review and Meta-Analysis.

BACKGROUND: Estimates of the serial interval distribution contribute to our understanding of the transmission dynamics of coronavirus disease 2019 (COVID-19). Here, we aimed to summarize the existing evidence on serial interval distributions and delays in case isolation for COVID-19. METHODS: We conducted a systematic review of the published literature and preprints in PubMed on 2 epidemiological parameters, namely, serial intervals and delay intervals relating to isolation of cases for COVID-19 from 1 January 2020 to 22 October 2020 following predefined eligibility criteria. We assessed the variation in these parameter estimates using correlation and regression analysis. RESULTS: Of 103 unique studies on serial intervals of COVID-19, 56 were included, providing 129 estimates. Of 451 unique studies on isolation delays, 18 were included, providing 74 estimates. Serial interval estimates from 56 included studies varied from 1.0 to 9.9 days, while case isolation delays from 18 included studies varied from 1.0 to 12.5 days, which were associated with spatial, methodological, and temporal factors. In mainland China, the pooled mean serial interval was 6.2 days (range, 5.1-7.8) before the epidemic peak and reduced to 4.9 days (range, 1.9-6.5) after the epidemic peak. Similarly, the pooled mean isolation delay related intervals were 6.0 days (range, 2.9-12.5) and 2.4 days (range, 2.0-2.7) before and after the epidemic peak, respectively. There was a positive association between serial interval and case isolation delay. CONCLUSIONS: Temporal factors, such as different control measures and case isolation in particular, led to shorter serial interval estimates over time. Correcting transmissibility estimates for these time-varying distributions could aid mitigation efforts.

Ventriculoperitoneal shunt is associated with increased cerebrospinal fluid protein level in HIV-infected cryptococcal meningitis patients.

BACKGROUND: The impact of ventriculoperitoneal shunt on cerebrospinal fluid (CSF) biochemical profiles in HIV-associated cryptococcal meningitis (HCM) patients remains unclear. METHODS: Twenty-nine HCM patients who underwent ventriculoperitoneal shunt (the VPS group) and 57 HCM patients who did not undergo ventriculoperitoneal shunt (the non-VPS group) were enrolled in this propensity score matching analysis. Demographic characteristics, symptoms, CSF biochemical profiles, and adverse events were compared between the two groups. The Kaplan-Meier method was used to analyze the survival rate. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for increased CSF protein levels. RESULTS: After 24 weeks of treatment, the intracranial pressure was significantly lower in the VPS group than in the non-VPS group (mmH2O; 155.0 [120.0-190.0] vs. 200.0 [142.5-290.0]; P = 0.025), and the rate of neuroimaging improvement was significantly higher in the VPS group (16/17 [94.1%] vs. 2/10 [20%]; P < 0.001). Furthermore, the 24-week cumulative survival rates were also significantly higher in the VPS group (96.6% vs. 83.5%, P = 0.025). Notably, the CSF protein levels were higher in the VPS group than in the non-VPS group at each examination time, and the CSF glucose was lower in the VPS group than in the non-VPS group even at the 12-week follow-up. In the multivariate analysis, we found that VPS placement was an independent risk factor for increased CSF protein (odds ratio [OR]: 27.8, 95% confidence interval [95% CI] 2.2-348.7; P = 0.010). CONCLUSIONS: VPS decreased the intracranial pressure, improved neuroimaging radiology and reduced the 24-week mortality in HCM patients. However, VPS significantly altered the CSF profiles, which could lead to misdiagnosis of tuberculous meningitis and some of them were diagnosed with immune reconstitution inflammatory syndrome. Physicians should be aware of these changes in the CSF profiles of patients with HCM undergoing VPS.

Nodal Memberships to Communities of Functional Brain Networks Reveal Functional Flexibility and Individualized Connectome.

Human brain network is organized as interconnected communities for supporting cognition and behavior. Despite studies on the nonoverlapping communities of brain network, overlapping community structure and its relationship to brain function remain largely unknown. With this consideration, we employed the Bayesian nonnegative matrix factorization to decompose the functional brain networks constructed from resting-state fMRI data into overlapping communities with interdigitated mapping to functional subnetworks. By examining the heterogeneous nodal membership to communities, we classified nodes into three classes: Most nodes in somatomotor and limbic subnetworks were affiliated with one dominant community and classified as unimodule nodes; most nodes in attention and frontoparietal subnetworks were affiliated with more than two communities and classified as multimodule nodes; and the remaining nodes affiliated with two communities were classified as bimodule nodes. This three-class paradigm was highly reproducible across sessions and subjects. Furthermore, the more likely a node was classified as multimodule node, the more flexible it will be engaged in multiple tasks. Finally, the FC feature vector associated with multimodule nodes could serve as connectome "fingerprinting" to gain high subject discriminability. Together, our findings offer new insights on the flexible spatial overlapping communities that related to task-based functional flexibility and individual connectome "fingerprinting."

Polymeric dexamethasone prodrugs attenuate lupus nephritis in MRL/lpr mice with reduced glucocorticoid toxicity.

Due to their potent immunosuppressive and anti-inflammatory effects, glucocorticoids (GCs) are the most widely used medications in treating lupus nephritis (LN). Long-term use of GCs, however, is associated with numerous off-target adverse effects. To reduce GCs' adverse effects, we previously developed two polymeric dexamethasone prodrug nanomedicines: N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based dexamethasone prodrug (P-Dex), and micelle-forming polyethylene glycol (PEG)-based dexamethasone prodrug (ZSJ-0228). Both P-Dex and ZSJ-0228 provided sustained amelioration of LN in lupus-prone NZB/W F1 mice with reduced GC-associated adverse effects. Here, we have extended our investigation to the MRL/lpr mouse model of LN. Compared to dose equivalent daily dexamethasone sodium phosphate (Dex) treatment, monthly P-Dex or ZSJ-0228 treatments were more effective in reducing proteinuria and extending the lifespan of MRL/lpr mice. Unlike the daily Dex treatment, ZSJ-0228 was not associated with measurable GC-associated adverse effects. In contrast, adrenal gland atrophy was observed in P-Dex treated mice.

Preclinical Dose-Escalation Study of ZSJ-0228, a Polymeric Dexamethasone Prodrug, in the Treatment of Murine Lupus Nephritis.

Glucocorticoids (GCs) are widely used in the clinical management of lupus nephritis (LN). Their long-term use, however, is associated with the risk of significant systemic side effects. We have developed a poly(ethylene glycol) (PEG)-based dexamethasone (Dex) prodrug (i.e., ZSJ-0228) and in a previous study, demonstrated its potential therapeutic efficacy in mice with established LN, while avoiding systemic GC-associated toxicity. In the present study, we have employed a dose-escalation design to establish the optimal dose-response relationships for ZSJ-0228 in treating LN and further investigated the safety of ZSJ-0228 in lupus-prone NZB/W F1 mice with established nephritis. ZSJ-0228 was intravenously (i.v.) administered monthly at four levels: 0.5 (L1), 1.0 (L2), 3.0 (L3), and 8.0 (L4) mg/kg/day Dex equivalent. For controls, mice were treated with i.v. saline every 4 weeks. In addition, a group of mice received intraperitoneal injections (i.p.) of Dex every day or i.v. injections of Dex every four weeks. Treatment of mice with LN with ZSJ-0228 dosed at L1 resulted in the resolution of proteinuria in 14% of the mice. Mice treated with ZSJ-0228 dosed at L2 and L3 levels resulted in the resolution of proteinuria in ∼60% of the mice in both groups. Treatment with ZSJ-0228 dosed at L4 resulted in the resolution of proteinuria in 30% of the mice. The reduction and/or resolution of the proteinuria, improvement in renal histological scores, and survival data indicate that the most effective dose range for ZSJ-0228 in treating LN in NZB/W F1 mice is between 1.0 and 3.0 mg/kg/day Dex equivalent. Typical GC-associated side effects (e.g., osteopenia, adrenal glands atrophy, etc.) were not observed in any of the ZSJ-0228 treatment groups, confirming its excellent safety profile.

Thermoresponsive Hydrogel-Based Local Delivery of Simvastatin for the Treatment of Periodontitis.

Except for routine scaling and root planing, there are few effective nonsurgical therapeutic interventions for periodontitis and associated alveolar bone loss. Simvastatin (SIM), one of the 3-hydroxy-3-methylglutaryl-cosenzyme A reductase inhibitors, which is known for its capacity as a lipid-lowering medication, has been proven to be an effective anti-inflammatory and bone anabolic agent that has shown promising benefits in mitigating periodontal bone loss. The local delivery of SIM into the periodontal pocket, however, has been challenging due to SIM's poor water solubility and its lack of osteotropicity. To overcome these issues, we report a novel SIM formulation of a thermoresponsive, osteotropic, injectable hydrogel (PF127) based on pyrophosphorolated pluronic F127 (F127-PPi). After mixing F127-PPi with F127 at a 1:1 ratio, the resulting PF127 was used to dissolve free SIM to generate the SIM-loaded formulation. The thermoresponsive hydrogel's rheologic behavior, erosion and SIM release kinetics, osteotropic property, and biocompatibility were evaluated in vitro. The therapeutic efficacy of SIM-loaded PF127 hydrogel on periodontal bone preservation and inflammation resolution was validated in a ligature-induced periodontitis rat model. Given that SIM is already an approved medication for hyperlipidemia, the data presented here support the translational potential of the SIM-loaded PF127 hydrogel for better clinical management of periodontitis and associated pathologies.

Reconstruction of Transmission Pairs for Novel Coronavirus Disease 2019 (COVID-19) in Mainland China: Estimation of Superspreading Events, Serial Interval, and Hazard of Infection.

BACKGROUND: Knowledge on the epidemiological features and transmission patterns of novel coronavirus disease (COVID-19) is accumulating. Detailed line-list data with household settings can advance the understanding of COVID-19 transmission dynamics. METHODS: A unique database with detailed demographic characteristics, travel history, social relationships, and epidemiological timelines for 1407 transmission pairs that formed 643 transmission clusters in mainland China was reconstructed from 9120 COVID-19 confirmed cases reported during 15 January-29 February 2020. Statistical model fittings were used to identify the superspreading events and estimate serial interval distributions. Age- and sex-stratified hazards of infection were estimated for household vs nonhousehold transmissions. RESULTS: There were 34 primary cases identified as superspreaders, with 5 superspreading events occurred within households. Mean and standard deviation of serial intervals were estimated as 5.0 (95% credible interval [CrI], 4.4-5.5) days and 5.2 (95% CrI, 4.9-5.7) days for household transmissions and 5.2 (95% CrI, 4.6-5.8) and 5.3 (95% CrI, 4.9-5.7) days for nonhousehold transmissions, respectively. The hazard of being infected outside of households is higher for people aged 18-64 years, whereas hazard of being infected within households is higher for young and old people. CONCLUSIONS: Nonnegligible frequency of superspreading events, short serial intervals, and a higher risk of being infected outside of households for male people of working age indicate a significant barrier to the identification and management of COVID-19 cases, which requires enhanced nonpharmaceutical interventions to mitigate this pandemic.

Serial Interval of COVID-19 among Publicly Reported Confirmed Cases.

We estimate the distribution of serial intervals for 468 confirmed cases of coronavirus disease reported in China as of February 8, 2020. The mean interval was 3.96 days (95% CI 3.53-4.39 days), SD 4.75 days (95% CI 4.46-5.07 days); 12.6% of case reports indicated presymptomatic transmission.

Risk for Transportation of Coronavirus Disease from Wuhan to Other Cities in China.

On January 23, 2020, China quarantined Wuhan to contain coronavirus disease (COVID-19). We estimated the probability of transportation of COVID-19 from Wuhan to 369 other cities in China before the quarantine. Expected COVID-19 risk is >50% in 130 (95% CI 89-190) cities and >99% in the 4 largest metropolitan areas.

Effects of Proactive Social Distancing on COVID-19 Outbreaks in 58 Cities, China.

Cities across China implemented stringent social distancing measures in early 2020 to curb coronavirus disease outbreaks. We estimated the speed with which these measures contained transmission in cities. A 1-day delay in implementing social distancing resulted in a containment delay of 2.41 (95% CI 0.97-3.86) days.

Modulating trap properties by Nd3+- Eu3+ co-doping in Sr2SnO4 host for optical information storage.

We report a novel Nd3+ and Eu3+ co-doped Sr2SnO4 (SSONE) phosphor showing the capability of "write-in" and "read-out" in optical information storage. As-prepared phosphors exhibit a dominant emission (PL) band centered at 596 nm under UV excitation, closely identical with its photo-stimulated luminescence (PSL) spectrum center (595 nm) upon near-infrared (NIR) light and thermal-stimulated luminescence (TSL) spectrum center (595 nm) under heat source. Remarkably, compared with Eu3+ single-doped phosphors, the co-doping strategy enhances the deep traps and also separates the deep traps with shallow traps, which are very crucial factors for optical information storage in electron trapping materials. Further, a demonstration confirmed the optical information storage capacity by photo- and thermal-stimulating the prepared phosphors filled in the designed patterns.

Low dispersion in the infectiousness of COVID-19 cases implies difficulty in control.

The individual infectiousness of coronavirus disease 2019 (COVID-19), quantified by the number of secondary cases of a typical index case, is conventionally modelled by a negative-binomial (NB) distribution. Based on patient data of 9120 confirmed cases in China, we calculated the variation of the individual infectiousness, i.e., the dispersion parameter k of the NB distribution, at 0.70 (95% confidence interval: 0.59, 0.98). This suggests that the dispersion in the individual infectiousness is probably low, thus COVID-19 infection is relatively easy to sustain in the population and more challenging to control. Instead of focusing on the much fewer super spreading events, we also need to focus on almost every case to effectively reduce transmission.

Network embedding for link prediction: The pitfall and improvement.

Link prediction plays a significant role in various applications of complex networks. The existing link prediction methods can be divided into two categories: structural similarity algorithms in network domain and network embedding algorithms in the field of machine learning. However, few researchers focus on comparing these two categories of algorithms and exploring the intrinsic relationship between them. In this study, we systematically compare the two categories of algorithms and study the shortcomings of network embedding algorithms. The results indicate that network embedding algorithms have poor performance in short-path networks. Then, we explain the reasons for this phenomenon by computing the Euclidean distance distribution of node pairs after a given network has been embedded into a vector space. In the vector space of a short-path network, the distance distribution of existent and nonexistent links are often less distinguishable, which can sharply reduce the algorithmic performance. In contrast, structural similarity algorithms, which are not restricted by the distance function, can represent node similarity accurately in short-path networks. To address the above pitfall of network embedding, we propose a novel method for link prediction aiming to supplement network embedding algorithms with local structural information. The experimental results suggest that our proposed algorithm has significant performance improvement in many empirical networks, especially in short-path networks. AUC and Precision can be improved by 36.7%-94.4% and 53.2%-207.2%, respectively.

Quantifying the Effects of Topology and Weight for Link Prediction in Weighted Complex Networks.

In weighted networks, both link weight and topological structure are significant characteristics for link prediction. In this study, a general framework combining null models is proposed to quantify the impact of the topology, weight correlation and statistics on link prediction in weighted networks. Three null models for topology and weight distribution of weighted networks are presented. All the links of the original network can be divided into strong and weak ties. We can use null models to verify the strong effect of weak or strong ties. For two important statistics, we construct two null models to measure their impacts on link prediction. In our experiments, the proposed method is applied to seven empirical networks, which demonstrates that this model is universal and the impact of the topology and weight distribution of these networks in link prediction can be quantified by it. We find that in the USAir, the Celegans, the Gemo, the Lesmis and the CatCortex, the strong ties are easier to predict, but there are a few networks whose weak edges can be predicted more easily, such as the Netscience and the CScientists. It is also found that the weak ties contribute more to link prediction in the USAir, the NetScience and the CScientists, that is, the strong effect of weak ties exists in these networks. The framework we proposed is versatile, which is not only used to link prediction but also applicable to other directions in complex networks.