Publications by authors named "Qian Lei"

307 Publications

Combined effects of hydralazine and nitrate on serum biochemistry and left ventricular remodeling in chronic heart failure patients.

Pak J Pharm Sci 2021 Jan;34(1(Special)):381-386

Heart Rehabilitation Center, Department of Cardiology, Shanghai Fourth People's Hospital, Tongji University, Shanghai, China.

To investigate the effects of hydralazine combined with nitrate on serum levels of Adropin and brain natriuretic peptide (BNP), left ventricular remodeling and prognosis in patients with chronic heart failure (CHF). 126 CHF patients were divided into control group (n=13, sodium nitroprusside) and combined treatment group (n=63, sodium nitroprusside ± hydralazine). Serum Adropin and BNP levels and left ventricular mass index (LVMI) of patients before treatment and 10 days after treatment were recorded, so did patient's end-point events. It was found that compared with those before treatment, the serum levels of Adropin, BNP, and LVMI in combined group and control group after 10 days of treatment were lower (P<0.05). The end-point event rate in the combined group was 19.05% (12/63). The serum levels of Adropin, BNP, and LVMI in the combined group with end-point events were higher than those of patients without end-point events (P<0.05). Spearman correlation analysis showed that serum levels of Adropin and BNP were positively correlated with LVMI and the end-point events rate (P<0.05). To sum up, hydralazine combined with sodium nitroprusside treatment can effectively reduce serum Adropin and BNP levels, and the risk of left ventricular remodeling and poor prognosis in patients with CHF.
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January 2021

Challenges in Phase 4 post-licensure safety studies using real world data in the United States: Hepatitis B vaccine example.

Vaccine X 2021 Aug 11;8:100101. Epub 2021 Jun 11.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, United States.

Post-licensure vaccine safety studies are essential to identify adverse events that may not have been detected in pre-licensure clinical trials and to address questions that arose during the pre-licensure phase. These studies are increasingly conducted using real-world data collected as part of routine health care delivery. However, design of post-licensure vaccine safety studies involves many pragmatic and scientific decisions, which must be made while balancing diverse stakeholder opinions. Challenges include selecting exposure and comparison groups, deciding on the most appropriate outcome, determining sample size and length of follow-up time, and other analytic considerations. As an example of this process and to inform other post-licensure vaccine safety studies in real-world settings, we discuss our experience with design of an FDA-required Phase 4 post-licensure safety study of a hepatitis B vaccine in a large integrated health care organization in the United States.
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http://dx.doi.org/10.1016/j.jvacx.2021.100101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233154PMC
August 2021

Clinical challenges in neoadjuvant immunotherapy for non-small cell lung cancer.

Chin J Cancer Res 2021 Apr;33(2):203-215

Cancer Center, the First Hospital of Jilin University, Changchun 130021, China.

Immune checkpoint inhibitors (ICIs), a type of immunotherapy, have become one of the most important therapeutic options for first- and second-line treatment of advanced non-small cell lung cancer (NSCLC). Recent clinical studies have shown that immunotherapy can offer substantial survival benefits to patients with early-stage or resectable advanced NSCLC. However, considering the importance of timing when using ICIs and their associated adverse events (AEs), the advantages and disadvantages of using these agents need to be weighed carefully when deciding the use of a combined treatment. In addition, the inconsistency between imaging assessment and pathological results poses further challenges to the evaluation of efficacy of neoadjuvant immunotherapy. It is also important to develop new methodologies and discover suitable biomarkers that can be used to evaluate survival outcomes of immunotherapy and identify patients who would benefit the most from this treatment. In this review, we aimed to summarize previous results of ongoing clinical trials on neoadjuvant immunotherapy for lung cancer and discuss the challenges and future perspectives of this therapeutic approach in the treatment of resectable NSCLC.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2021.02.08DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181868PMC
April 2021

Long-Term High-Altitude Exposure Does Not Increase the Incidence of Atrial Fibrillation Associated with Organic Heart Diseases.

High Alt Med Biol 2021 Jun 17. Epub 2021 Jun 17.

Anesthesia and Operation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

Wang, Man, Mengxue Liu, Jia Huang, Dan Fan, Shengzhong Liu, Tao Yu, Keli Huang, Xinchuan Wei, and Qian Lei. Long-term high-altitude exposure does not increase the incidence of atrial fibrillation associated with organic heart diseases. 00:000-000, 2021.- Atrial fibrillation (AF) is one of the most common arrhythmias and is associated with several complications following cardiac surgery. However, the differences in the incidence of AF associated with organic heart diseases between highland and lowland populations have not been comprehensively studied. In this retrospective study, a total of 2,316 highland and lowland patients who underwent cardiac surgery between January 2013 and December 2018 in a single center were enrolled. According to the altitude of residence, patients were divided into high-altitude (>1,500 m) and low-altitude (<1,500 m) groups. A propensity score matching analysis was performed to estimate the association of lifetime high-altitude exposure with AF. Among the enrolled patients, 239 (10.9%) were from a high-altitude plateau, while 1,946 (89.1%) were from a low-altitude area. There were statistical differences in age, gender, European System for Cardiac Operative Risk Evaluation, and other factors, between the two groups ( < 0.05). According to the propensity score, 237 patients in the high-altitude group were successfully matched to 237 patients in the low-altitude group without significant difference in baseline data ( > 0.05). Among the matched patients, 125 patients (26.4%) suffered from AF, with 66 (27.8%) in the high-altitude group and 59 (24.9%) in the low-altitude group. The incidence of AF was statistically similar between the two groups and not significantly influenced by long-term high-altitude exposure (odds ratio 1.07; 95% confidence interval 0.71-1.60,  > 0.05). Long-term high-altitude exposure did not significantly increase the occurrence of AF in patients with organic heart diseases. Clinical Trial No. ChiCTR1900028612.
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http://dx.doi.org/10.1089/ham.2020.0228DOI Listing
June 2021

Mo-doped CoO ultrathin nanosheet arrays anchored on nickel foam as a bi-functional electrode for supercapacitor and overall water splitting.

J Colloid Interface Sci 2021 Jun 5;602:355-366. Epub 2021 Jun 5.

College of Geography and Environmental Sciences, Zhejiang Normal University, Jinhua 321004, China; College of Chemistry and Life Science, Zhejiang Normal University, Jinhua 321004, China. Electronic address:

Simple preparation, favorable price and environmental protection have been a long-term challenge in the field of electrochemistry. Herein, we studied and prepared a bifunctional Mo-doped CoO ultrathin nanosheets, which has been validated as an effective binder-free electrode material for electrocatalytic water splitting and supercapacitors. The material has a large specific surface area, high electrical conductivity and exposure to more active sites, breaking down the limited performance and range of use of transition metal oxides. Benefiting from intriguing ultrathin property and conductivity, OER and HER process of 0.4Mo-CoO have a small Tafel slope of 83.7 and 98 mV dec, respectively. The current density at 10 mA cm show a low overpotential of 315 and 79 mV and significant stability. The water electrolytic device requires a potential of 1.64 V to reach 10 mA cm, and the potential change is negligible after 12 h of continuous electrolysis. In addition, the manifest improved electrochemical performance of 0.3Mo-CoO as supercapacitor electrode material shows high areal capacitance 2815 mF cm at 1 mA cm, excellent rate performance (85% at 10 mA cm) and retains 90% of the initial capacitance by cycling 5000 at a current density of 10 mA cm. Moreover, 0.3Mo-CoO||0.3Mo-CoO symmetrical supercapacitor has a maximum volumetric energy density of 1.25 mW h cm at a power density of 7.1 mW cm and superior cycle life. The influence of doping on electrochemical performance was studied by changing the content of doped metal ions, which is of great significance for the exploration of supercapacitor and electrocatalytic hydrolysis of bifunctional electrode materials.
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http://dx.doi.org/10.1016/j.jcis.2021.06.019DOI Listing
June 2021

Multidifferentiation potential of dental-derived stem cells.

World J Stem Cells 2021 May;13(5):342-365

Department of Endodontics, Stomatological Hospital, Southern Medical University, Guangzhou 510280, Guangdong Province, China.

Tooth-related diseases and tooth loss are widespread and are a major public health issue. The loss of teeth can affect chewing, speech, appearance and even psychology. Therefore, the science of tooth regeneration has emerged, and attention has focused on tooth regeneration based on the principles of tooth development and stem cells combined with tissue engineering technology. As undifferentiated stem cells in normal tooth tissues, dental mesenchymal stem cells (DMSCs), which are a desirable source of autologous stem cells, play a significant role in tooth regeneration. Researchers hope to reconstruct the complete tooth tissues with normal functions and vascularization by utilizing the odontogenic differentiation potential of DMSCs. Moreover, DMSCs also have the ability to differentiate towards cells of other tissue types due to their multipotency. This review focuses on the multipotential capacity of DMSCs to differentiate into various tissues, such as bone, cartilage, tendon, vessels, neural tissues, muscle-like tissues, hepatic-like tissues, eye tissues and glands and the influence of various regulatory factors, such as non-coding RNAs, signaling pathways, inflammation, aging and exosomes, on the odontogenic/osteogenic differentiation of DMSCs in tooth regeneration. The application of DMSCs in regenerative medicine and tissue engineering will be improved if the differentiation characteristics of DMSCs can be fully utilized, and the factors that regulate their differentiation can be well controlled.
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http://dx.doi.org/10.4252/wjsc.v13.i5.342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176842PMC
May 2021

Super Stretchable and Compressible Hydrogels Inspired by Hook-and-Loop Fasteners.

Langmuir 2021 06 15;37(25):7760-7770. Epub 2021 Jun 15.

Polymer Program, Institute of Materials Science, University of Connecticut, Storrs, Connecticut 06269, United States.

Inspired by hook-and-loop fasteners, we designed a hydrogel network containing α-zirconium phosphate (ZrP) two-dimensional nanosheets with a high density of surface hydroxyl groups serving as nanopatches with numerous "hooks," while polymer chains with plentiful amine functional groups serve as "loops." Our multiscale molecular simulations confirm that both the high density of hydroxyl groups on nanosheets and the large number of amine functional groups on polymer chains are essential to achieve reversible interactions at the molecular scale, functioning as nano hook-and-loop fasteners to dissipate energy. As a result, the synthesized hydrogel possesses superior stretchability (>2100% strain), resilience to compression (>90% strain), and durability. Remarkably, the hydrogel can sustain >5000 cycles of compression with torsion in a solution mimicking synovial fluid, thus promising for potential biomedical applications such as artificial articular cartilage. This hook-and-loop model can be adopted and generalized to design a wide range of multifunctional materials with exceptional mechanical properties.
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http://dx.doi.org/10.1021/acs.langmuir.1c00924DOI Listing
June 2021

Construction of a novel asymmetric imidazole-cored AIE probe for ratiometric imaging of endogenous leucine aminopeptidase.

Chem Commun (Camb) 2021 Jul;57(54):6608-6611

Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, P. R. China. and Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Changsha 410078, China.

We report a rational strategy to deliberately construct the first asymmetric tetraarylimidazole-based AIE probe, integrating AIE behavior in synergy with ESIPT character to image endogenous LAP for the first time. It offered good sensitivity and selectivity, and concomitantly, was applied successfully for real-time tracking of LAP in the cisplatin-induced liver injury zebrafish model.
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http://dx.doi.org/10.1039/d1cc01940fDOI Listing
July 2021

Is there a role for the p75 neurotrophin receptor in mediating degeneration during oxidative stress and after hypoxia?

J Neurochem 2021 Jun 10. Epub 2021 Jun 10.

School of Biomedical Sciences, Faculty of Medicine and Queensland Brain Institute, Clem Jones Centre for Ageing Dementia Research, The University of Queensland, Brisbane, Qld., Australia.

Cholinergic basal forebrain (cBF) neurons are particularly vulnerable to degeneration following trauma and in neurodegenerative conditions. One reason for this is their characteristic expression of the p75 neurotrophin receptor (p75 ), which is up-regulated and mediates neuronal death in a range of neurological and neurodegenerative conditions, including dementia, stroke and ischaemia. The signalling pathway by which p75 signals cell death is incompletely characterised, but typically involves activation by neurotrophic ligands and signalling through c-Jun kinase, resulting in caspase activation via mitochondrial apoptotic signalling pathways. Less well appreciated is the link between conditions of oxidative stress and p75 death signalling. Here, we review the literature describing what is currently known regarding p75 death signalling in environments of oxidative stress and hypoxia to highlight the overlap in signalling pathways and the implications for p75 signalling in cBF neurons. We propose that there is a causal relationship and define key questions to test this assertion.
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http://dx.doi.org/10.1111/jnc.15451DOI Listing
June 2021

miR-10396b-3p inhibits mechanical stress-induced ligamentum flavum hypertrophy by targeting IL-11.

FASEB J 2021 06;35(6):e21676

Department of Orthopedics, The Third Affiliated Hospital, Southern Medical University, Academy of Orthopedics, Guangzhou, China.

Ligamentum flavum hypertrophy (LFH) leads to lumbar spinal stenosis (LSS) caused by LF tissue inflammation and fibrosis. Emerging evidence has indicated that dysregulated microRNAs (miRNAs) have an important role in inflammation and fibrosis. Mechanical stress (MS) has been explored as an initiating step in LFH pathology progression; the inflammation-related miRNAs induced after mechanical stress have been implicated in fibrosis pathology. However, the pathophysiological mechanism of MS-miRNAs-LFH remains to be elucidated. Using miRNAs sequencing analysis and subsequent confirmation with qRT-PCR assays, we identified the decreased expression of miR-10396b-3p and increased expression of IL-11 (interleukin-11) as responses to the development of LSS in hypertrophied LF tissues. We also found that IL-11 is positively correlated with fibrosis indicators of collagen I and collagen III. The up-regulation of miR-10396b-3p significantly decreased the level of IL-11 expression, whereas miR-10396b-3p down-regulation increased IL-11 expression in vitro. Luciferase reporter assay indicates that IL-11 is a direct target of miR-10396b-3p. Furthermore, cyclic mechanical stress inhibits miR-10396b-3p and induces IL-11, collagen I, and collagen III in vitro. Our results showed that overexpression of miR-10396b-3p suppresses MS-induced LFH by inhibiting collagen I and III via the inhibition of IL-11. These data suggest that the MS-miR-10396b-3p-IL-11 axis plays a key role in the pathological progression of LFH.
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http://dx.doi.org/10.1096/fj.202100169RRDOI Listing
June 2021

[CDs-BOC Nanophotocatalyst Activating Persulfate Under Visible Light for the Efficient Degradation of Typical PPCPs].

Huan Jing Ke Xue 2021 Jun;42(6):2885-2895

School of Environmental and Municipal Engineering, Xi'an University of Architecture and Technology, Xi'an 710055, China.

A new type of CDs-BOC photocatalyst was synthesized in a convenient two-step method of hydrothermal and calcination processes. Carbon quantum dots (CDs) were used to modify BiOCl nanosheets. The as-prepared nanocomposite was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), UV-vis diffuse reflectance spectroscopy (DRS), X-ray photoelectron spectroscopy (XPS), and photoluminescence spectroscopy (PL), which showed that CDs were successfully introduced. The absorption edge of 7% CDs-BOC nanocomposite was broadened to the visible light region (424 nm), and the charge separation efficiency was remarkably improved. To improve the degradation efficiency of organic pollutants, persulfate (PS) was also introduced into the system. Due to the excellent photocatalytic ability of the nanocatalyst, the photogenerated electrons can effectively activate the PS to produce more reactive oxidizing species (ROS). Under visible light (>420 nm) irradiation, 5 mg·L acetaminophen (AAP) can be completely removed within 20 min. Via radical quenching experiments and electron paramagnetic resonance spectroscopy (EPR), the major ROS are determined to be·OH,·SO,·O, and h, and the photo-degradation mechanism is proposed. The excellent photocatalytic performance of the CDs-BOC/PS system shows broad practical potential for wastewater treatment.
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http://dx.doi.org/10.13227/j.hjkx.202011047DOI Listing
June 2021

An interdomain helix in IRE1α mediates the conformational change required for the sensor's activation.

J Biol Chem 2021 Jan-Jun;296:100781. Epub 2021 May 14.

Division of Cell Pathology, Children's Hospital of Philadelphia and University of Pennsylvania, Civic Center Boulevard, Philadelphia, Pennsylvania, USA. Electronic address:

The unfolded protein response plays an evolutionarily conserved role in homeostasis, and its dysregulation often leads to human disease, including diabetes and cancer. IRE1α is a major transducer that conveys endoplasmic reticulum stress via biochemical signals, yet major gaps persist in our understanding of how the detection of stress is converted to one of several molecular outcomes. It is known that, upon sensing unfolded proteins via its endoplasmic reticulum luminal domain, IRE1α dimerizes and then oligomerizes (often visualized as clustering). Once assembled, the kinase domain trans-autophosphorylates a neighboring IRE1α, inducing a conformational change that activates the RNase effector domain. However, the full details of how the signal is transmitted are not known. Here, we describe a previously unrecognized role for helix αK, located between the kinase and RNase domains of IRE1α, in conveying this critical conformational change. Using constructs containing mutations within this interdomain helix, we show that distinct substitutions affect oligomerization, kinase activity, and the RNase activity of IRE1α differentially. Furthermore, using both biochemical and computational methods, we found that different residues at position 827 specify distinct conformations at distal sites of the protein, such as in the RNase domain. Of importance, an RNase-inactive mutant, L827P, can still dimerize with wildtype monomers, but this mutation inactivates the wildtype molecule and renders leukemic cells more susceptible to stress. We surmise that helix αK is a conduit for the activation of IRE1α in response to stress.
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http://dx.doi.org/10.1016/j.jbc.2021.100781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203841PMC
May 2021

Trends in Influenza Vaccine Uptake and Severe Influenza-Related Outcomes at Kaiser Permanente Southern California, 2007-2017.

Perm J 2021 May;25

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA.

Introduction: Major efforts to increase influenza vaccine uptake among Kaiser Permanente Southern California (KPSC) members have been undertaken in recent years. However, whether these improvements translate to a decline in severe influenza-related outcomes has not been examined. We aimed to understand the impact of the influenza vaccination program at KPSC by examining influenza vaccine uptake and 3 severe influenza-related outcomes.

Methods: We conducted an ecologic trend analysis to understand influenza vaccine uptake and influenza-related hospitalization, intensive care unit (ICU) admission, and mortality for each influenza season (2007-2017). The same cohort was followed from the influenza season to the noninfluenza season immediately afterward while using the noninfluenza season as the comparison group. We also assessed the within-season correlation between influenza vaccine uptake and influenza-related outcomes.

Results: Influenza vaccine uptake rose from 23.9% to 45.5%, and all 3 influenza-related outcome rates declined (hospitalization: 35.4-26.8/10,000 patients; ICU: 5.9-5.2/10,000 patients; and mortality: 3.4-2.3/10,000 patients). Influenza vaccine uptake was negatively correlated with hospitalization (-0.32, p < 0.001) and mortality (-0.29, p = 0.001). However, once we adjusted for the noninfluenza season, the results of the correlation analysis were no longer statistically significant.

Conclusion: Although we could not establish a statistically significant inverse relationship between influenza vaccination and severe influenza-related outcomes over the study period, our findings indicate an overall decline in influenza-related outcomes over the study period, suggesting improvements in both preventive and acute care quality at KPSC.
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http://dx.doi.org/10.7812/TPP/20.154DOI Listing
May 2021

Correction: Impact of the COVID-19 Pandemic on Health Care Utilization in a Large Integrated Health Care System: Retrospective Cohort Study.

J Med Internet Res 2021 May 5;23(5):e30101. Epub 2021 May 5.

Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA, United States.

[This corrects the article DOI: 10.2196/26558.].
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http://dx.doi.org/10.2196/30101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135025PMC
May 2021

Impact of the COVID-19 Pandemic on Health Care Utilization in a Large Integrated Health Care System: Retrospective Cohort Study.

J Med Internet Res 2021 04 29;23(4):e26558. Epub 2021 Apr 29.

Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA, United States.

Background: The COVID-19 pandemic has caused an abrupt reduction in the use of in-person health care, accompanied by a corresponding surge in the use of telehealth services. However, the extent and nature of changes in health care utilization during the pandemic may differ by care setting. Knowledge of the impact of the pandemic on health care utilization is important to health care organizations and policy makers.

Objective: The aims of this study are (1) to evaluate changes in in-person health care utilization and telehealth visits during the COVID-19 pandemic and (2) to assess the difference in changes in health care utilization between the pandemic year 2020 and the prepandemic year 2019.

Methods: We retrospectively assembled a cohort consisting of members of a large integrated health care organization, who were enrolled between January 6 and November 2, 2019 (prepandemic year), and between January 5 and October 31, 2020 (pandemic year). The rates of visits were calculated weekly for four settings: inpatient, emergency department (ED), outpatient, and telehealth. Using Poisson models, we assessed the impact of the pandemic on health care utilization during the early days of the pandemic and conducted difference-in-deference (DID) analyses to measure the changes in health care utilization, adjusting for the trend of health care utilization in the prepandemic year.

Results: In the early days of the pandemic, we observed significant reductions in inpatient, ED, and outpatient utilization (by 30.2%, 37.0%, and 80.9%, respectively). By contrast, there was a 4-fold increase in telehealth visits between weeks 8 (February 23) and 12 (March 22) in 2020. DID analyses revealed that after adjusting for prepandemic secular trends, the reductions in inpatient, ED, and outpatient visit rates in the early days of the pandemic were 1.6, 8.9, and 367.2 visits per 100 person-years (P<.001), respectively, while the increase in telehealth visits was 272.9 visits per 100 person-years (P<.001). Further analyses suggested that the increase in telehealth visits offset the reduction in outpatient visits by week 26 (June 28, 2020).

Conclusions: In-person health care utilization decreased drastically during the early period of the pandemic, but there was a corresponding increase in telehealth visits during the same period. By end-June 2020, the combined outpatient and telehealth visits had recovered to prepandemic levels.
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http://dx.doi.org/10.2196/26558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086778PMC
April 2021

Pediatric Vaccination During the COVID-19 Pandemic.

Pediatrics 2021 Apr 15. Epub 2021 Apr 15.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California.

Objectives: The impact of the coronavirus disease 2019 pandemic on vaccination coverage, critical to preventing vaccine-preventable diseases, has not been assessed during the reopening period.

Methods: Vaccine uptake and vaccination coverage for recommended vaccines and for measles-containing vaccines at milestone ages were assessed in a large cohort of children aged 0 to 18 years in Southern California during January to August 2020 and were compared with those in the same period in 2019. Differences in vaccine uptake and vaccination coverage (recommended vaccines and measles-containing vaccines) in prepandemic (January to March), stay-at-home (April to May), and reopening (June to August) periods in 2020 and 2019 were compared.

Results: Total and measles-containing vaccine uptake declined markedly in all children during the pandemic period in 2020 compared with 2019, but recovered in children aged 0 to 23 months. Among children aged 2 to 18 years, measles-containing vaccine uptake recovered, but total vaccine uptake remained lower. Vaccination coverage (recommended and measles-containing vaccines) declined and remained reduced among most milestone age cohorts ≤24 months during the pandemic period, whereas recommended vaccination coverage in older children decreased during the reopening period in 2020 compared with 2019.

Conclusions: Pediatric vaccine uptake decreased dramatically during the pandemic, resulting in decreased vaccination coverage that persisted or worsened among several age cohorts during the reopening period. Additional strategies, including immunization tracking, reminders, and recall for needed vaccinations, particularly during virtual visits, will be required to increase vaccine uptake and vaccination coverage and reduce the risk of outbreaks of vaccine-preventable diseases.
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http://dx.doi.org/10.1542/peds.2020-047092DOI Listing
April 2021

Lack of Macrophage Migration Inhibitory Factor Reduces Susceptibility to Ventricular Arrhythmias During the Acute Phase of Myocardial Infarction.

J Inflamm Res 2021 7;14:1297-1311. Epub 2021 Apr 7.

Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, People's Republic of China.

Background: Macrophages are involved in inflammatory responses and play a crucial role in aggravating ventricular arrhythmias (VAs) after myocardial infarction (MI). Macrophage migration inhibitory factor (MIF) participates in inflammatory responses during acute MI. In the present study, we hypothesized that knockout (KO) of MIF may prevent VAs during the acute phase of MI by inhibiting macrophage-derived pro-inflammatory mediators.

Methods And Results: We demonstrated that MIF-KO mice in a mouse model of MI exhibited a significant decrease in susceptibility to VAs both in vivo (84.6% vs 40.7%, < 0.05) and ex vivo (86.7% vs 40.0%, < 0.05) at day 3 after MI compared with that in wild-type (WT) mice. Both WT and MIF-KO mice presented similar left ventricular contractility, peri-infarct myocardial fibrosis and sympathetic reinnervation, and circulating and local norepinephrine levels during the acute phase of MI. Meanwhile, MIF-KO mice had inhibited macrophage aggregation, alleviated connexin 43 (Cx43) redistribution, and reduced level of pro-inflammatory mediators, including tumor necrosis factor-α and interleukin-1β ( < 0.05) at day 3 after MI. The differences in susceptibility to VAs, expression of pro-inflammatory mediators, and Cx43 redistribution after MI between WT and MIF-KO mice disappeared by macrophage depletion with clodronate liposomes in both groups. Furthermore, the pro-inflammatory activity of cultured peritoneal macrophages was inhibited by MIF deficiency and recovered with replenishment of exogenous MIF in vitro.

Conclusion: In conclusion, we found that lack of MIF reduced the susceptibility to VAs in mouse heart during the acute phase of MI by inhibiting pro-inflammatory activity of macrophages and improving gap-junction and electrical remodeling.
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http://dx.doi.org/10.2147/JIR.S304553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039209PMC
April 2021

miR-24 targets HMOX1 to regulate inflammation and neurofunction in rats with cerebral vasospasm after subarachnoid hemorrhage.

Am J Transl Res 2021 15;13(3):1064-1074. Epub 2021 Mar 15.

Department of Cerebrovascular Diseases, Brain Hospital Affiliated to Tongji University Shanghai City, China.

Objective: To investigate the effects of miR-24 and HMOX1 on the inflammatory response and neurological function in rats with cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH).

Methods: Fifteen Sprague-Dawley rats were randomly assigned to the sham group (sham operation, treated with normal saline). Rat model of SAH-induced CVS was established in 90 rats, and these rats were randomly divided into the model, miR-24 NC (treated with miR-24-NC vector), miR-24 inhibitor (treated with miR-24 inhibitor vector), HMOX-NC (treated with HMOX1-NC vector), oe-HMOX1 (treated with HMOX1 overexpression vector), and miR-24 inhibitor + si-HMOX1 (treated with miR-24 inhibitor and si-HMOX1 vectors) groups. Adenoviral vectors containing the target sequences were injected into the hippocampus of the rats in the corresponding groups. Dual-luciferase reporter assay was conducted to verify the relationship between miR-24 and HMOX1. The learning and memory abilities, neurological function, cerebral edema, permeability of blood-brain barrier, myeloperoxidase activity, and levels of miR-24, HMOX1, interleukin-6, tumor necrosis factor-α, superoxide dismutase, and malondialdehyde in rats were examined.

Results: miR-24 could negatively regulate HMOX1 expression. SAH-induced CVS was accompanied with increased miR-24 expression and decreased HMOX1 expression. Inhibiting miR-24 expression or enhancing the expression of its down streaming target, HMOX1, could partly reverse the increased oxidation and inflammation as well as functional deficits in the rats. Moreover, the effects of miR-24 inhibitor could be reversed by inhibiting HMOX1 expression.

Conclusion: miR-24 downregulation can promote HMOX1 expression, thereby decreasing the inflammatory response and improving the neurological function of rats with CVS after SAH.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014398PMC
March 2021

Periplocymarin protects against myocardial fibrosis induced by β-adrenergic activation in mice.

Biomed Pharmacother 2021 Jul 8;139:111562. Epub 2021 Apr 8.

Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China. Electronic address:

Periplocymarin is an effective component of Periplocae Cortex, which was wildly used as an ingredient in Traditional Chinese Medicine. Our group previously reported that periplocymarin exerted cardiotonic role via promoting calcium influx. However, its exact role in the pathogenesis of myocardial fibrosis has not been elucidated yet. The present study was aimed at determining the potential effect and underlying mechanism of periplocymarin in isoproterenol (ISO)-induced myocardial fibrosis. C57BL/6 mice were subcutaneously injected with ISO (5 mg/kg/day) or saline for 1 week. The early-to-atrial wave ratio (E/A ratio) measured by echocardiography revealed that ISO-induced heart stiffness was remarkably reversed by administration of periplocymarin (5 mg/kg/day). Masson trichrome staining exhibited that treatment of periplocymarin reduced the excessive deposition of extracellular matrix (ECM). Further investigations employing real-time PCR and western blot demonstrated that periplocymarin suppressed the expression of fibrosis related genes (Col1a1, Col3a1, Acta2 and Tgfb1) and proteins (Collagen I, Collagen III, α-SMA and TGF-β1) induced by ISO. Metabolomics analysis demonstrated that periplocymarin ameliorated the disorders triggered by ISO and many of the differential metabolic substances were involved in amino acid, glucose and lipid metabolism. Further analysis using network pharmacology revealed that three key genes, namely NOS2, NOS3 and Ptgs2, may be the potential targets of periplocymarin and responsible for the disorders. Validation using heart tissues showed that the mRNA expression of NOS3 was decreased while Ptgs2 was increased upon ISO treatment, which were reversed by periplocymarin. Moreover, the expression of COX-2 (Ptgs2 encoded protein) was consistent with the aspect of Ptgs2 mRNA, while eNOS (NOS3 encoded protein) expression was unchanged. In vitro studies exhibited that periplocymarin exerts anti-fibrotic function via regulating at least eNOS and COX-2 in cardiomyocyte. Taken together, periplocymarin protects against myocardial fibrosis induced by β-adrenergic activation, the potential mechanism was that periplocymarin targeted on, at least eNOS and COX-2, to improve the metabolic processes of cardiomyocyte and thus attenuated the myocardial fibrosis. Our study highlighted that periplocymarin is a potential therapeutic agent for the prevention of myocardial fibrosis.
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http://dx.doi.org/10.1016/j.biopha.2021.111562DOI Listing
July 2021

Templateless, Plating-Free Fabrication of Flexible Transparent Electrodes with Embedded Silver Mesh by Electric-Field-Driven Microscale 3D Printing and Hybrid Hot Embossing.

Adv Mater 2021 May 7;33(21):e2007772. Epub 2021 Apr 7.

Shandong Engineering Research Center for Additive Manufacturing, Qingdao University of Technology, Qingdao, 266520, China.

Flexible transparent electrodes (FTEs) with an embedded metal mesh are considered a promising alternative to traditional indium tin oxide (ITO) due to their excellent photoelectric performance, surface roughness, and mechanical and environmental stability. However, great challenges remain for achieving simple, cost-effective, and environmentally friendly manufacturing of high-performance FTEs with embedded metal mesh. Herein, a maskless, templateless, and plating-free fabrication technique is proposed for FTEs with embedded silver mesh by combining an electric-field-driven (EFD) microscale 3D printing technique and a newly developed hybrid hot-embossing process. The final fabricated FTE exhibits superior optoelectronic properties with a transmittance of 85.79%, a sheet resistance of 0.75 Ω sq , a smooth surface of silver mesh (R  ≈ 18.8 nm) without any polishing treatment, and remarkable mechanical stability and environmental adaptability with a negligible increase in sheet resistance under diverse cyclic tests and harsh working conditions (1000 bending cycles, 80 adhesion tests, 120 scratch tests, 100 min ultrasonic test, and 72 h chemical attack). The practical viability of this FTE is successfully demonstrated with a flexible transparent heater applied to deicing. The technique proposed offers a promising fabrication strategy with a cost-effective and environmentally friendly process for high-performance FTE.
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http://dx.doi.org/10.1002/adma.202007772DOI Listing
May 2021

Ultrasonographic assessment in vivo of the excursion and tension of flexor digitorum profundus tendon on different rehabilitation protocols after tendon repair.

J Hand Ther 2021 Jan 26. Epub 2021 Jan 26.

Department of Orthopaedics, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, Jiangsu, China. Electronic address:

Study Design: Interpretive description study.

Purpose: In management of patients with flexion tendon injuries, passive, control active and active motion protocols were proposed after repair to minimize tendon adhesion. The purpose of this study was to compare the excursion distance and the tension of Flexor Digitorum Profundus (FDP) during simulated active and passive motion using ultrasonography techniques using normal subjects.

Methods: Ultrasonographic assessment of FDP tendon of the middle finger was performed at the wrist level on 20 healthy college students using 3 types of treatment protocols: modified Kleinert protocol, modified Duran protocol, and active finger flexion protocol. The excursion distance was measured following the musculotendinous junction of FDP using the B mode ultrasound system. The elasticity of FDP tendon was measured using the shear wave elastography technique. The excursion distance and the elasticity value were compared among 3 protocols using one-way ANOVA analysis.

Results: Twelve male and 8 female students with mean age of 22.6 ± 1.8 years were invited to join the study. The excursion distance of FDP was 21.82 ± 3.77 mm using the active finger flexion protocol, 8.59 ± 2.59 mm using the modified Duran protocol, and 12.26 ± 2.71 mm using the modified Kleinert protocol. The elasticity was significantly higher in extension position when compared to passive flexion positions, but found lower than active flexion position.

Discussion: The active finger protocol was found to require strongest tension of the tendon and with longest excursion. There was similar tension generated using both passive motion protocols. The modified Duran protocol appeared to create less excursion upon movements than the modified Kleinert approach using the objective ultrasonic evaluation. It is suggested that if the surgical repair was strong and without any complications, the active flexion protocol might work best to regain tension excursion. However, if there are complex problems involved, then the Kleinert approach or Duran approach would be chosen.
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http://dx.doi.org/10.1016/j.jht.2021.01.006DOI Listing
January 2021

Uncatalyzed and acid-aided microwave hydrothermal carbonization of orange peel waste.

Waste Manag 2021 May 17;126:106-118. Epub 2021 Mar 17.

Dept. of Bioresource Engineering, McGill University, Macdonald Campus, 21111 Lakeshore road, Sainte-Anne-de-Bellevue, Quebec H9X 3V9, Canada.

Orange, one of the most important fruit categories to be consumed across the world, when processed produces 50% of its weight as waste. Current waste management options for orange peel waste are inadequate to use the waste in wholesome and its disposal might lead to other environmental concerns. Here, we present microwave hydrothermal carbonization as an alternative to utilize the orange peel waste. Further, using citric acid to catalyze the microwave hydrothermal carbonization resulted in 30% higher maximal yield of hydrochar, and the hydrochar produced had better elemental, proximate and energy properties than hydrochar made during uncatalyzed microwave hydrothermal carbonization. Further, structural analysis revealed that citric acid promoted the formation of nanospheres during microwave hydrothermal carbonization. Taken together, microwave hydrothermal carbonization of orange peel waste using citric acid as a catalyst might not only help address the waste management concerns for orange peel waste, but also can produce end products of potential commercial value.
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http://dx.doi.org/10.1016/j.wasman.2021.02.058DOI Listing
May 2021

Efficacy of electrochemical membrane bioreactor for virus removal from wastewater: Performance and mechanisms.

Bioresour Technol 2021 Jun 10;330:124946. Epub 2021 Mar 10.

State Key Laboratory of Pollution Control and Resource Reuse, Shanghai Institute of Pollution Control and Ecological Security, School of Environmental Science and Engineering, Tongji University, 1239 Siping Road, Shanghai 200092, China; International Joint Research Center for Sustainable Urban Water System, Shanghai 200092, China. Electronic address:

Wastewater treatment facilities play pivotal roles in preventing the transmission of water-borne viruses and protecting human health. In this study, a new electrochemical membrane bioreactor (EMBR) was proposed to achieve a long-lasting and efficient removal of virus from wastewater. Results showed that applying a low electric field (2.0 V) in EMBR system could achieve ~100% removal efficiency at both batch tests and continuous flow experiments. In contrast, the control MBR, without the exertion of electric field, exhibited a very low removal efficiency (19.8% on average). Moreover, the fouling in EMBR was significantly mitigated, which enabled its operation duration almost 3 times longer than that of the control. Further explorations suggested that the reactive oxidants generated on electrodes in the EMBR system were mainly responsible for MS2 removal. This study demonstrated the potential of utilizing the EMBR process to achieve an enhanced virus disinfection efficiency during the wastewater treatment process.
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http://dx.doi.org/10.1016/j.biortech.2021.124946DOI Listing
June 2021

The Application of Nanotechnology for the Diagnosis and Treatment of Brain Diseases and Disorders.

Front Bioeng Biotechnol 2021 2;9:629832. Epub 2021 Mar 2.

Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, China.

Brain is by far the most complex organ in the body. It is involved in the regulation of cognitive, behavioral, and emotional activities. The organ is also a target for many diseases and disorders ranging from injuries to cancers and neurodegenerative diseases. Brain diseases are the main causes of disability and one of the leading causes of deaths. Several drugs that have shown potential in improving brain structure and functioning in animal models face many challenges including the delivery, specificity, and toxicity. For many years, researchers have been facing challenge of developing drugs that can cross the physical (blood-brain barrier), electrical, and chemical barriers of the brain and target the desired region with few adverse events. In recent years, nanotechnology emerged as an important technique for modifying and manipulating different objects at the molecular level to obtain desired features. The technique has proven to be useful in diagnosis as well as treatments of brain diseases and disorders by facilitating the delivery of drugs and improving their efficacy. As the subject is still hot, and new research findings are emerging, it is clear that nanotechnology could upgrade health care systems by providing easy and highly efficient diagnostic and treatment methods. In this review, we will focus on the application of nanotechnology in the diagnosis and treatment of brain diseases and disorders by illuminating the potential of nanoparticles.
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http://dx.doi.org/10.3389/fbioe.2021.629832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960921PMC
March 2021

Cost-effectiveness analysis of different sequences of osimertinib administration for epidermal growth factor receptor-mutated non-small-cell lung cancer.

Exp Ther Med 2021 Apr 10;21(4):343. Epub 2021 Feb 10.

Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.

Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is clinically effective in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the use of this treatment is limited by its high cost. A cost-effectiveness analysis of different sequences of osimertinib administration in China and the United States was conducted in the present study. Markov models were established based on data from the FLAURA and AURA3 trials. First-line osimertinib was compared with both first-generation EGFR-TKIs and second-line osimertinib after the failure of first-generation EGFR-TKIs. The analysis also considered different payment modalities available in China. Additionally, one-way and probability sensitivity analyses, with a willingness-to-pay threshold (WTP) of three times the per capita gross domestic product [$27,783/quality-adjusted life year (QALY) for China and $100,000/QALY for the United States], were performed. The first-line osimertinib group displayed higher QALYs and costs than those of the first-generation EGFR-TKI group. The first generation EGFR-TKI group displayed an incremental cost-effectiveness ratio (ICER) of $212,252/QALY in China and $151,922/QALY in the United States. In addition, the ICERs were negative in the second-line osimertinib group, with higher QALYs and lower costs compared with those in the first-line osimertinib group. Furthermore, osimertinib company donation was of benefit in China, with an average cost-effectiveness of $836/QALY. The one-way sensitivity analysis highlighted the influence of utilities in different states. First-line osimertinib could be cost-effective either with higher WTP or a price reduction of 68% in China and 9% in the United States. Although first-line osimertinib therapy could have health benefits, it was not cost-effective compared with first-line first-generation EGFR-TKIs and second-line osimertinib therapy. However, paying via company donation may be a good choice in China.
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http://dx.doi.org/10.3892/etm.2021.9774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903425PMC
April 2021

Extracellular vesicles deposit to rejuvenate aged bone marrow-derived mesenchymal stem cells and slow age-related degeneration.

Sci Transl Med 2021 01;13(578)

Center for Artificial Intelligence Biology, Hubei Bioinformatics and Molecular Imaging Key Laboratory, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.

Stem cell senescence increases alongside the progressive functional declines that characterize aging. The effects of extracellular vesicles (EVs) are now attracting intense interest in the context of aging and age-related diseases. Here, we demonstrate that neonatal umbilical cord (UC) is a source of EVs derived from mesenchymal stem cells (MSC-EVs). These UC-produced MSC-EVs (UC-EVs) contain abundant anti-aging signals and rejuvenate senescing adult bone marrow-derived MSCs (AB-MSCs). UC-EV-rejuvenated AB-MSCs exhibited alleviated aging phenotypes and increased self-renewal capacity and telomere length. Mechanistically, UC-EVs rejuvenate AB-MSCs at least partially by transferring proliferating cell nuclear antigen () into recipient AB-MSCs. When tested in therapeutic context, UC-EV-triggered rejuvenation enhanced the regenerative capacities of AB-MSCs in bone formation, wound healing, and angiogenesis. Intravenously injected UC-EVs conferred anti-aging phenotypes including decreased bone and kidney degeneration in aged mice. Our findings reveal that UC-EVs are of high translational value in anti-aging intervention.
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http://dx.doi.org/10.1126/scitranslmed.aaz8697DOI Listing
January 2021

Completion of the two-dose recombinant zoster vaccine series in adults 50 years and older.

Vaccine 2021 02 11;39(6):926-932. Epub 2021 Jan 11.

Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA 91101, USA.

Background: In 2017, a new adjuvanted recombinant zoster vaccine (RZV) was recommended for adults ≥50 years as two-dose series 2-6 months apart. We evaluated two-dose RZV completion and factors associated with completion.

Methods: The study included Kaiser Permanente Southern California members ≥50 years who received an RZV dose during April-November 2018 and had continuous membership 12 months before to 9 months after the first RZV dose. Completion was defined as receipt of the second dose ≥4 weeks to 9 months after the first dose (allowing 3-month grace period). Characteristics including age, sex, race/ethnicity, Medicaid status, neighborhood level income and education, comorbidities, history of zoster, health care utilization before and after the first dose, receipt of influenza vaccine, vaccination month (supply shortage proxy), concomitant vaccine, medical center, and medically attended reactions, pain, or gout after the first dose were compared between completers and non-completers. Adjusted odds ratios and 95% confidence intervals for factors associated with completion were estimated by multivariable logistic regression.

Results: Among 31,120 first dose recipients, 67.2% completed the series within 9 months. In adjusted analyses, higher completion was associated with White compared with Black or Hispanic race/ethnicity, higher neighborhood income and education, no chronic pulmonary disease, diabetes, or dementia, more outpatient visits and fewer emergency department visits before or after the first dose, no hospitalizations after the first dose, receipt of influenza vaccine, receipt of the first dose in June-November rather than April-May 2018, and no concomitant vaccine with the first dose. Systemic reactions or pain after the first dose was not associated with completion.

Conclusion: Completion of RZV series appears suboptimal in the early phase of implementation. Despite similar accessibility in a health care system, completion varied by race/ethnicity, socioeconomic status, health status, and care seeking behavior, suggesting areas to target for improvement.
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http://dx.doi.org/10.1016/j.vaccine.2020.12.076DOI Listing
February 2021

Prevalence and incidence of microvascular and macrovascular complications over 15 years among patients with incident type 2 diabetes.

BMJ Open Diabetes Res Care 2021 01;9(1)

Research and Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA.

Introduction: Type 2 diabetes (T2D) is a common condition that, if left untreated or poorly managed, can lead to adverse microvascular and macrovascular complications. We estimated the prevalence and incidence of microvascular and macrovascular complications among patients newly diagnosed with T2D within a US integrated healthcare system.

Research Design And Methods: We conducted a retrospective cohort study among patients newly diagnosed with T2D between 2003 and 2014. We evaluated 13 complications, including chronic kidney disease (CKD), cardiovascular disease (CVD), and all-cause mortality through 2018. Multivariable Cox proportional hazards models were used to study factors associated with complications.

Results: We identified 135 199 patients with incident T2D. The mean age was 58 years, and 48% were women. The prevalence of CKD was the highest of the complications at the time of T2D diagnosis (prevalence=12.3%, 95% CI 12.2% to 12.5%), while the prevalence of CVD was among the lowest at 3.3% (95% CI 3.2% to 3.3%). The median time to incidence of a T2D complication ranged from 3.0 to 5.2 years. High incidence rates (95% CI) of T2D complications included peripheral neuropathy (26.9, 95% CI 26.5 to 27.3 per 1000 person-years (PY)), CKD (21.2, 95% CI 20.9 to 21.6 per 1000 PY), and CVD (11.9, 95% CI 11.7 to 12.2 per 1000 PY). The trend of 5-year incidence rates of T2D complications by diagnosis year decreased over time (p value<0.001). Older age, non-Hispanic white race/ethnicity, sex, higher A1C, smoking, and hypertension were associated with increased CKD and CVD incidence.

Conclusion: Though incidence rates of T2D complications were lower in more recent years (2010-2014), a significant proportion of patients had complications at T2D diagnosis. Earlier preventive therapies as well as managing modifiable factors may help delay the development and progression of T2D complications.
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http://dx.doi.org/10.1136/bmjdrc-2020-001847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783518PMC
January 2021

Anesthesia of a high-altitude area inhabitant who underwent aortic dissection emergency surgery in a low-altitude area.

J Int Med Res 2020 Dec;48(12):300060520979871

Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

Heart surgery in patients from high-altitude areas is more challenging than usual. Few studies have been published on this issue, and none of them have discussed the effect of an altitude change (from high to low altitude) on a patient's physiology or its effects on a patient's perioperative management. Here, we present the case of a 46-year-old man who was a long-time resident of Tibetan area in Sichuan (altitude >3000 m) who underwent Stanford type A aortic dissection emergency surgery on the plain. Anesthetic management occurred through monitoring of the bispectral index (BIS) and transesophageal echocardiography (TEE), and we used a relatively loose fluid hydration strategy. The surgery was performed using cardiopulmonary bypass (CPB), deep hypothermia (DH), and selective antegrade cerebral perfusion. The most prominent anesthesia challenges for these patients are physiological changes due to habitation in an high-altitude environment (chronic hypoxemia), which can cause hyperhemoglobinemia, polycythemia, hypercoagulable blood, and even pulmonary hypertension, cor pulmonale, or congestive heart failure. Optimized perioperative management and close cooperation among the entire cardiac medical team were the key factors in the successful management of this rare case.
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http://dx.doi.org/10.1177/0300060520979871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758670PMC
December 2020

Inference of Naturally Acquired Immunity Using a Self-matched Negative-Control Design.

Epidemiology 2021 03;32(2):168-178

From the Center for Computational Biology, College of Engineering, University of California, Berkeley, Berkeley, CA.

Host adaptive immune responses may protect against infection or disease when a pathogen is repeatedly encountered. The hazard ratio of infection or disease, given previous infection, is typically sought to estimate the strength of protective immunity. However, variation in individual exposure or susceptibility to infection may introduce frailty bias, whereby a tendency for infections to recur among individuals with greater risk confounds the causal association between previous infection and susceptibility. We introduce a self-matched "case-only" inference method to control for unmeasured individual heterogeneity, making use of negative-control endpoints not attributable to the pathogen of interest. To control for confounding, this method compares event times for endpoints due to the pathogen of interest and negative-control endpoints during counterfactual risk periods, defined according to individuals' infection history. We derive a standard Mantel-Haenszel (matched) odds ratio conveying the effect of prior infection on time to recurrence. We compare performance of this approach to several proportional hazards modeling frameworks and estimate statistical power of the proposed strategy under various conditions. In an example application, we use the proposed method to reestimate naturally acquired protection against rotavirus gastroenteritis using data from previously published cohort studies. This self-matched negative-control design may present a flexible alternative to existing approaches for analyzing naturally acquired immunity, as well as other exposures affecting the distribution of recurrent event times.
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http://dx.doi.org/10.1097/EDE.0000000000001305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850593PMC
March 2021
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