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In this paper, an effective numerical method for solving the variable-order(VO) fractional reaction diffusion equation with the Caputo fractional derivative is constructed and analyzed. Based on the generalized alternating numerical flux, we get a fully discrete local discontinuous Galerkin scheme for the problem. From a practical standpoint, the generalized alternating numerical flux, which is distinct from the purely alternating numerical flux, has a more extensive scope. For $ 0 < \alpha(t) < 1 $, we prove that the method is unconditionally stable and the errors attain $ (k+1) $-th order of accuracy for piecewise $ P^k $ polynomials. Finally, some numerical experiments are performed to show the effectiveness and verify the accuracy of the method.

Aim: C1q/TNF-related protein 6 (CTRP6) is a novel adipokine involved in insulin resistance. Thus, we aim to investigate the expression profile of CTRP6 in the plasma, adipose tissue and placenta of GDM patients and mice. Methods: Chinese Han pregnant women (GDM n = 9, control n = 10) with a scheduled caesarean section delivery were recruited. A number of high-fat diet (HFD) induced-pregnancy C57BL/6 mice were chosen as an animal model of GDM. Circulating levels of CTRP6 and adiponectin were examined by ELISA. CTRP6 expression in adipose tissue and placenta were detected by real-time qPCR and WB. Result: Plasma CTRP6 levels were decreased during the first and second trimesters in mice, as well as the second and third trimesters in patients, while they were increased at delivery in GDM patients and mice. Plasma CTRP6 levels were significantly correlated with WBC, systolic pressure, diastolic pressure and fasting blood glucose. Moreover, CTRP6 mRNA expression in the subcutaneous (sWAT) and omental white adipose tissue (oWAT), as well as in the placenta, was significantly higher in GDM human patients at cesarean delivery. Furthermore, the mRNA expression of Ctrp6 was increased in the sWAT and visceral WAT (vWAT), whilst decreased in the interscapular brown adipose tissue (iBAT), of GDM mice at cesarean delivery. Conclusion: Dynamically expressed CTRP6 may be served as a candidate target for treatment of GDM.

Abstract Background Waldenström macroglobulinemia (WM) is a rare and incurable indolent B-cell malignancy. The molecular pathogenesis and the role of immunosuppressive microenvironment in WM development are still incompletely understood. Methods The multicellular ecosystem in bone marrow (BM) of WM were delineated by single-cell RNA-sequencing (scRNA-seq) and investigated the underlying molecular characteristics. Results Our data uncovered the heterogeneity of malignant cells in WM, and investigated the kinetic co-evolution of WM and immune cells, which played pivotal roles in disease development and progression. Two novel subpopulations of malignant cells, CD19+CD3+ and CD138+CD3+, co-expressing T-cell marker genes were identified at single-cell resolution. Pseudotime-ordered analysis elucidated that CD19+CD3+ malignant cells presented at an early stage of WM-B cell differentiation. Colony formation assay further identified that CD19+CD3+ malignant cells acted as potential WM precursors. Based on the findings of T cell marker aberrant expressed on WM tumor cells, we speculate the long-time activation of tumor antigen-induced immunosuppressive microenvironment that is involved in the pathogenesis of WM. Therefore, our study further investigated the possible molecular mechanism of immune cell dysfunction. A precursor exhausted CD8-T cells and functional deletion of NK cells were identified in WM, and CD47 would be a potential therapeutic target to reverse the dysfunction of immune cells. Conclusions Our study facilitates further understanding of the biological heterogeneity of tumor cells and immunosuppressive microenvironment in WM. These data may have implications for the development of novel immunotherapies, such as targeting pre-exhausted CD8-T cells in WM.

Abstract Background Surgical incision, endotracheal intubation, structural changes in the oral cavity, and other factors lead to a divergence in oral care between patients after oral surgery and ordinary inpatients. High-quality oral care can reduce the incidence of incision infection and ventilator-associated pneumonia. However, there is a lack of guidelines or expert consensus on oral care after oral cancer surgery. Therefore, the aim of this study was to assess the practicing situation of nurses in the intensive care unit (ICU) for postoperative patients with oral cancer and their need for training. Methods A multicenter cross-sectional study design was conducted in 19 ICUs of 11 tertiary hospitals from Henan province in China. Data were collected from 173 nurses and 19 head nurses online using a structured questionnaire. Mann–Whitney U and Kruskal–Wallis H tests were performed to analyze the data using SPSS (Version 25.0). Results Seven ICUs (36.8%) developed evaluation regulations for the oral care of postoperative patients with oral cancer, and eight ICUs (42.1%) described the operating standards. A total of 173 nurses completed the questionnaire, and the median score was 75 (68, 78). Almost all of the examined nurses (91.2%) assessed patients’ oral hygiene at a fixed time, while in 52.0% and 28.3% of nurses, the first oral care and frequency of oral care after surgery was determined based on the individual patient’s situation. More than half of the nurses (55.5%) spent approximately 5–10 min conducting oral care for patients. Physiological saline solution (82.7%), swabbing (91.9%), and oral care package with cotton ball (86.1%) were the most popular oral care mouthwash, method, and tool, respectively. Nurses sought help from senior nurses (87.3%) and doctors (83.8%), mostly to solve difficulties of oral care. Moreover, 76.9% of the nurses believed that the lack of knowledge and skills surrounding oral care was the main barrier for nurses to implement oral care. The majority of participants (69.4%) had never received continuing education or training in oral care for postoperative patients with oral cancer, and almost all (98.8%) of the respondents stated their preference to receive training in standardized oral care skills. Indications and contraindications (84.4%), tools (81.5%), and mouthwash (80.9%) of oral care were the items that the respondents were most eager to learn about. Approximately three quarters of nurses preferred scenario simulation practice as the training method. Conclusion Although the participants had high oral care scores for postoperative patients with oral cancer, there was great diversity in the practice. The lack of oral care knowledge was deemed the main barrier in delivering quality oral care, and the educational need was stated by almost all participants. We suggest that a standard protocol or clinical practice guidelines for oral care for postoperative patients with oral cancer should be developed, and nurses should be educated to equip them with professional knowledge and skills.

Abstract Background Genomic prediction (GP) and genome-wide association (GWA) analyses are currently being employed to accelerate breeding cycles and to identify alleles or genomic regions of complex traits in forest trees species. Here, 1490 interior lodgepole pine (Pinus contorta Dougl. ex. Loud. var. latifolia Engelm) trees from four open-pollinated progeny trials were genotyped with 25,099 SNPs, and phenotyped for 15 growth, wood quality, pest resistance, drought tolerance, and defense chemical (monoterpenes) traits. The main objectives of this study were to: (1) identify genetic markers associated with these traits and determine their genetic architecture, and to compare the marker detected by single- (ST) and multiple-trait (MT) GWA models; (2) evaluate and compare the accuracy and control of bias of the genomic predictions for these traits underlying different ST and MT parametric and non-parametric GP methods. GWA, ST and MT analyses were compared using a linear transformation of genomic breeding values from the respective genomic best linear unbiased prediction (GBLUP) model. GP, ST and MT parametric and non-parametric (Reproducing Kernel Hilbert Spaces, RKHS) models were compared in terms of prediction accuracy (PA) and control of bias. Results MT-GWA analyses identified more significant associations than ST. Some SNPs showed potential pleiotropic effects. Averaging across traits, PA from the studied ST-GP models did not differ significantly from each other, with generally a slight superiority of the RKHS method. MT-GP models showed significantly higher PA (and lower bias) than the ST models, being generally the PA (bias) of the RKHS approach significantly higher (lower) than the GBLUP. Conclusions The power of GWA and the accuracy of GP were improved when MT models were used in this lodgepole pine population. Given the number of GP and GWA models fitted and the traits assessed across four progeny trials, this work has produced the most comprehensive empirical genomic study across any lodgepole pine population to date.

BackgroundThe association between high-density lipoprotein cholesterol (HDL-C) and adverse cardiovascular outcomes is understudied. Based on cohort studies, the current study aimed to investigate the association of extremely high HDL-C with all-cause, atherosclerotic cardiovascular disease (CVD) mortality, and stroke risk.MethodsA systematic literature search in Embase, PubMed, Cochrane Library, and Web of Science was performed to collect relevant cohort studies published before August 20, 2022. A random-effects model was used to pool relative risks (RRs) and 95% confidence intervals (CIs).ResultsA total of 17 cohort studies involving 19,630,829 participants were included, encompassing 18,547,132 total deaths (1,328,036 CVD deaths). All-cause mortality, CVD mortality, and stroke risk in the extremely high HDL-C group were increased by 15% (RR = 1.15, 95% CI:1.05–1.25), 14% (RR = 1.14, 95% CI:0.96–1.35) and 14% (RR = 1.14, 95% CI:0.82–1.58), compared to the normal HDL-C group. In subgroup analyses, extremely high HDL-C was associated with a reduced risk of CVD mortality in women and a lower risk of stroke in men compared to normal HDL-C levels.ConclusionsThe extremely high levels of HDL-C were associated with elevated risks of all-cause mortality, CVD mortality, and stroke. More well-designed studies are needed to confirm our findings.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=370201, identifier: CRD42022370201.

For a long time, people have suffered from uncertainty, complexity, and a low success rate in generating and screening antibodies against small molecules, which have become the core bottlenecks of immunochemistry. Here, the influence of antigen preparation on antibody generation was investigated at both molecular and submolecular levels. Neoepitopes (amide-containing neoepitopes) formed in the preparation of complete antigens are one of the most important factors limiting the efficiency of generating hapten-specific antibodies, which was verified by different haptens, carrier proteins, and conjugation conditions. Amide-containing neoepitopes present electron-dense structural components on the surface of prepared complete antigens and, therefore, induce the generation of the corresponding antibody with much higher efficiency than target hapten. Crosslinkers should be carefully selected and not overdosed. According to these results, some misconceptions in the conventional anti-hapten antibody production were clarified and corrected. By controlling the content of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) during the synthesis of immunogen to limit the formation of amide-containing neoepitopes, the efficiency of hapten-specific antibody generation could be significantly improved, which verified the correctness of the conclusion and provided an efficient strategy for antibody preparation. The result of the work is of scientific significance in the preparation of high-quality antibodies against small molecules.

BackgroundAlcohol use disorder (AUD) has become a significant global factor in various diseases. As a non-pharmacological therapy, certain therapeutic potential has been found in acupuncture; however, in-depth mechanistic studies related to acupuncture for patients with AUD are still insufficient.MethodsBased on a randomized control design and a multi-omics analysis plan, this protocol details the recruitment (42 AUD patients), group allocation (21 in acupuncture group vs. 21 in sham acupuncture group), intervention and follow-up (replacement drugs as a normal treatment, 2 weeks acupuncture duration, and 3 month follow-up), and data collection and analytical processes. For the clinical outcomes, in addition to the time required for alcohol withdrawal symptoms to subside as the primary outcome, changes in the alcohol withdrawal symptoms, alcohol craving, mood dysfunction, sleep disorder, fatigue, self-efficacy, gastrointestinal symptoms, the quality of life, and the relapse outcomes will be compared between the groups to confirm the acupuncture clinical effectiveness on alcohol withdraw. The gut microbiome and the fecal metabolomics will also be assessed to explore the association of the structure and the function of gut microflora and the mediation of acupuncture effect on AUD fully utilizing gut microflora multi-modal data and clinical information, via the combination of multi-omics methods, feature screening algorithms and appropriate models.DiscussionThe results of this study may help to strengthen clinical evidence of the mechanism of acupuncture intervention in patients with AUD, through understanding of the regulatory mechanism of acupuncture in the gut microbiome and its metabolism as well as AUD-related clinical manifestations.Trial registrationChinese Clinical Trial Registry ChiCTR2200058120. Registered on 24 Mar 2022.

In this paper, a fully discrete local discontinuous Galerkin finite element method is proposed to solve the KdV-Burgers-Kuramoto equation with variable-order Riemann-Liouville time fractional derivative. The method proposed in this paper is based on the finite difference method in time and local discontinuous Galerkin method in space. For all ϵ(t)∈(0,1) with variable order, we prove the scheme is unconditional stable and convergent. Finally, numerical examples are provided to verify the theoretical analysis and the order of convergence for the proposed method.

BackgroundPropionic acidemia (PA) is an inherited autosomal recessive metabolic disorder that is classified as early-onset or late-onset, depending on the onset time of clinical symptoms. It clinically manifests as numerous lesions in the brain, pancreas, liver, and muscle. Muscle biopsies show myopathic changes, which help to distinguish late-onset propionic acidemia from other metabolic diseases involving muscles.Case presentationA 19-year-old Chinese girl was admitted to the hospital because of poor eating and fatigue. Head magnetic resonance imaging suggested metabolic diseases, and we administered symptomatic support treatment. Her symptoms gradually worsened, and she began to show convulsions and disturbances of consciousness. Muscle pathology showed myopathy-like changes. The presence of organic acids in the blood and urine suggested PA. Genetic analyses identified two compound heterozygous mutations in the patient's PCCB gene, confirming the diagnosis of delayed PA.ConclusionsThe muscle pathological examination of late-onset PA provides valuable information that is helpful for distinguishing delayed-onset PA from metabolic diseases. In the absence of a history of trauma, subdural hematoma may be a very rare complication of late-onset PA and can be regarded as a poor prognostic sign; therefore, it is suggested to perform head computed tomography as part of the routine neurological evaluation of PA patients.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron damage. Due to the complexity of the ALS, so far the etiology and underlying pathogenesis of sporadic ALS are not completely understood. Recently, many studies have emphasized the role of inflammatory networks, which are comprised of various inflammatory molecules and proteins in the pathogenesis of ALS. Inflammatory molecules and proteins may be used as independent predictors of patient survival and might be used in patient stratification and in evaluating the therapeutic response in clinical trials. This review article describes the latest advances in various inflammatory markers in ALS and its animal models. In particular, this review discusses the role of inflammatory molecule markers in the pathogenesis of the disease and their relationship with clinical parameters. We also highlight the advantages and disadvantages of applying inflammatory markers in clinical manifestations, animal studies, and drug clinical trials. Further, we summarize the potential application of some inflammatory biomarkers as new therapeutic targets and therapeutic strategies, which would perhaps expand the therapeutic interventions for ALS.

ObjectiveTo determine the diagnostic accuracy of serological tests for coronavirus disease-2019 (COVID-19).MethodsPubMed, Embase and the Cochrane Library were searched from January 1 2020 to September 2 2022. We included studies that measured the sensitivity, specificity or both qualities of a COVID-19 serological test and a reference standard of a viral culture or reverse transcriptase polymerase chain reaction (RT–PCR). The risk of bias was assessed by using quality assessment of diagnostic accuracy studies 2 (QUADAS-2). The primary outcomes included overall sensitivity and specificity, as stratified by the methods of serological testing [enzyme-linked immunosorbent assays (ELISAs), lateral flow immunoassays (LFIAs) or chemiluminescent immunoassays (CLIAs)] and immunoglobulin classes (IgG, IgM, or both). Secondary outcomes were stratum-specific sensitivity and specificity within the subgroups, as defined by study or participant characteristics, which included the time from the onset of symptoms, testing via commercial kits or an in-house assay, antigen target, clinical setting, serological kit as the index test and the type of specimen for the RT–PCR reference test.ResultsEight thousand seven hundred and eighty-five references were identified and 169 studies included. Overall, we judged the risk of bias to be high in 47.9 % (81/169) of the studies, and a low risk of applicability concerns was found in 100% (169/169) of the studies. For each method of testing, the pooled sensitivity of the ELISAs ranged from 81 to 82%, with sensitivities ranging from 69 to 70% for the LFIAs and 77% to 79% for the CLIAs. Among the evaluated tests, IgG (80–81%)-based tests exhibited better sensitivities than IgM-based tests (66–68%). IgG/IgM-based CLIA had the highest sensitivity [87% (86–88%)]. All of the tests displayed high specificity (97–98%). Heterogeneity was observed in all of the analyses. The detection of nucleocapsid protein (77–80%) as the antigen target was found to offer higher sensitivity results than surface protein detection (66–68%). Sensitivity was higher in the in-house assays (78–79%) than in the commercial kits (47–48%).ConclusionAmong the evaluated tests, ELISA and CLIA tests performed better in terms of sensitivity than did the LFIA. IgG-based tests had higher sensitivity than IgM-based tests, and combined IgG/IgM test-based CLIA tests had the best overall diagnostic test accuracy. The type of sample, serological kit and timing of use of the specific tests were associated with the diagnostic accuracy. Due to the limitations of the serological tests, other techniques should be quickly approved to provide guidance for the correct diagnosis of COVID-19.

Immune-mediated necrotizing myopathy (IMNM) is a class of idiopathic inflammatory myopathies. According to the types of antibodies in serum, IMNM can be divided into three subtypes: anti-signal recognition particle (SRP) necrotizing myopathy, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) necrotizing myopathy, and serum antibody-negative necrotizing myopathy. Different subtypes of IMNM have common characteristics, but the specific pathological mechanisms differ. Anti-SRP necrotizing myopathy is an important type of IMNM. At present, the pathogenesis of the disease is unclear. Most views suggest that the disease is mainly caused by an autoimmune response; therefore, the therapeutic strategy is primarily immune regulation. Recent studies have implicated non-immune mechanisms such as endoplasmic reticulum stress and autophagy in the occurrence and development of the disease. Here, we review what is known about the pathogenesis of anti-SRP necrotizing myopathy and summarize the latest research progress, aiming to better understand the disease and provide new ideas for treatment targets.

IntroductionMultiple myeloma (MM) is still an incurable plasma cell malignancy. The efficacy of immunotherapy on MM remains unsatisfactory, and the underlying molecular mechanisms still are not fully understood.MethodsIn this study, we delineated the dynamic features of immune cell in MM bone marrow (BM) along with elevated tumor cell infiltration by single-cell RNA sequencing (scRNA-seq), and investigated the underlying mechanisms on dysfunction of immune cells associated with myelomagenesis.ResultsWe found that immune cells were activated in those patients with low infiltration of tumor cells, meanwhile suppressed with elevated infiltration of MM cells, which facilitated MM escaping from immune surveillance. Besides PD-1, abnormal expression of PIM kinases, KLRB1 and KLRC1 were involved in the defect of immune cells in MM patients. Importantly, we found aberrant metabolic processes were associated with the immunosuppressive microenvironment in MM patients. Disordered amino acid metabolism promoted the dysfunction of cytotoxicity CD8 T cells as well as lipid metabolism disorder was associated with the dysregulation of NK and DCs in MM. As metabolic checkpoints, PIM kinases would be potential effective strategies for MM immunotherapy.DiscussionIn summary, redressing the disordered metabolism should be the key points to get promising effects in immune-based therapies.

BackgroundPatients with MMT often face difficulties such as sleep disturbance, headaches, and difficulty in complete abstinence from drugs. Research has shown that acupuncture can mitigate side effects while attenuating methadone dependence. It also has a synergistic and attenuated effect on methadone maintenance treatment (MMT). Exploring the predictors of the efficacy of acupuncture intervention in MMT might help clinicians and patients promote acupuncture-assisted participation in MMT, and improve clinical treatment strategies for MMT.ObjectiveTo describe the effect of potential predictors on MMT after acupuncture intervention by building a decision-tree model of data from A Clinical Study of Acupuncture-assisted MMT.Design, setting, and participantsIn this randomized controlled trial, 135 patients with MMT underwent acupuncture at the Substance Dependence Department of Guangzhou Huiai Hospital in Guangzhou, Guangdong Province, China.InterventionA total of 135 patients were 1:1 randomly assigned to either an acupuncture plus routine care group (acupuncture plus methadone) or a routine group (methadone only) for 6 weeks, and followed up for 10 weeks. Sex, age, education level, route of previous opioid use, years of opioid use, and MMT time were recorded before the trial.Outcome measurements and statistical analysisAll analyses were based on the intention-to-treat (ITT) population. The two decision tree models used the change of methadone dosage and the VAS score for opioid desire as response variables, respectively, and the evaluation criteria were positive effect (decreased by ≥20%) and no effect (decreased by

BackgroundPost-stroke shoulder pain (PSSP) is characterized by shoulder pain on the hemiplegic side, which can limit physical activity in patients with stroke. Acupuncture combined with rehabilitation training (AR) has been widely used in PSSP, but the evidence of its effectiveness is still unclear.ObjectiveThe study aimed to evaluate the effect and safety of AR vs. rehabilitation training (RT) alone on PSSP.MethodsWe searched PubMed, the Cochrane Library, the Chinese Biological Medicine Database (CBM), the Chinese Scientific Journal Database (VIP), China National Knowledge Infrastructure (CNKI), and the WAN FANG database for relevant studies from their inception to February 2022. Only randomized controlled trials (RCTs) comparing the effect of AR with RT alone on PSSP were considered. The primary outcome was shoulder pain. Secondary outcomes included upper limb motor function, activities of daily living (ADL), shoulder range of motion (ROM), and adverse events (AEs). Subgroup analysis and sensitivity analysis were also conducted. Quality assessment was implemented based on Cochrane risk of bias (ROB) criteria, which consist of seven items. When more than four items in a study were judged as low ROB, the overall quality of this study was considered low risk.ResultsA total of 40 studies were included in the qualitative analysis, and 35 (87.5%) studies with 2,554 patients were included in the meta-analysis. Of the 40 studies, 14 (35.0%) were of moderate-to-high quality. The meta-analysis results showed that AR is better than RT alone in reducing shoulder pain (MD −1.32, 95% CI −1.58 to −1.07), improving upper limb motor function (MD 6.81, 95% CI 4.95–8.67), ADL (MD 11.17, 95% CI 9.44–12.91), and shoulder ROM (internal rotation: MD 10.48, 95% CI 8.14–12.83; backward extension: MD 7.82, 95% CI 6.00–9.64; anteflexion: MD 12.88, 95% CI 5.47–20.29; external rotation: MD 11.40, 95% CI 6.17–16.64; abduction: MD 16.96, 95% CI 8.61–25.31) without obvious AEs.ConclusionAR may be better than RT alone for the improvement of shoulder pain, upper limb motor function, ADL, and shoulder ROM, without obvious AEs in patients with PSSP. However, considering the clinical and statistical heterogeneity, our findings need to be interpreted with caution. More rigorous RCTs in this area should be conducted in the future.Systematic review registration[www.crd.york.ac.uk], identifier [CRD42022326763].

BackgroundSocial support is an important factor affecting individual mental health. However, the relationship between social support and mental health in frontline healthcare workers (FHW) during the coronavirus disease 2019 (COVID-19) pandemic has garnered less attention. In this study, we aimed to investigate the level of social support and the prevalence of depression and anxiety in FHW during the COVID-19 pandemic and determine the factors affecting the relationship between social support, depression, and anxiety.MethodsA cross-sectional study using an online survey was conducted to collect data from FHW between 15 February and 31 March 2020 in China. The data included demographic factors, Self-rated Depression Scale (SDS), Self-rated Anxiety Scale (SAS), and Social Support Rate Scale (SSRS). Spearman correlation test was performed to determine the correlation among SAS, SDS, and SSRS scores. Multiple linear regression analysis was performed to determine the relationship among demographic factors, social support, depression, and anxiety in FHW.ResultsOf all 201 participants, 44 (21.9%) had depressive symptoms and 32 (15.9%) had anxiety symptoms. The average total SSRS scores among FHW were lower than that of the norms of the Chinese general population (37.17 ± 7.54 versus 44.38 ± 8.38, P < 0.001). Marital status positively affected the SSRS score (β = 7.395, P < 0.01). Age over 40 years old negatively affected the SSRS score (β = −5.349, P = 0.017). The total SSRS score, subjective social support score, objective social support score, and support utilization score among FHW negatively correlated with the SAS score and SDS score (P < 0.05). A lower support utilization score was significantly associated with high anxiety and depressive symptoms (β = −0.869, P = 0.024; β = −1.088, P = 0.035, respectively).ConclusionDuring the COVID-19 pandemic, FHW experienced depression, anxiety, and inadequate social support. The marital status and age had a major impact on social support. Social support was inversely associated with depression and anxiety. Improving the mental health of FHW by strengthening social support is crucial. Future studies are needed to investigate how to improve the level of social support and mental health condition of FHW facing public health emergencies in the future.

BackgroundNicotine dependence is an addictive behavioral disease facilitated by habitually smoking cigarettes. In many countries, acupuncture and auricular acupressure have attracted growing attention as complementary or alternative treatments for smoking cessation; however, there is a lack of rigorous randomized, controlled studies evaluating the combination of these two interventions specifically for smoking cessation. The aim of this study is to evaluate the efficacy and safety of using acupuncture combined with auricular acupressure (A&AA) to increase the rates of smoking cessation and ultimately reduce the rates of relapse.MethodsThis is a multicentre, prospective, parallel, randomized, controlled trial. A total of 360 patients with severe nicotine dependence will be randomized into test (A&AA) or control (nicotine replacement therapy, NRT) groups. The test group will be treated with A&AA twice weekly, while the control group will use an NRT patch daily. All treatments will be administered for 8 weeks, with a follow-up period of 4 months. The primary outcome will be the smoking abstinence rate at week 24, with a combined safety assessment. The secondary outcomes will be smoking cessation rates at other timepoints, saliva cortisone test results, and scores on the Fagerstrom Test for Nicotine Dependence, the Autonomy over Tobacco Scale, the Hamilton Anxiety Rating Scale, the Self-rating Anxiety Scale, and the Pittsburgh Sleep Quality Index. The cost of treatment will also be used to evaluate the economic effects of different smoking cessation interventions. Statistical analysis on the data collected from both the intention-to-treat (all randomly assigned patients) and per-protocol (patients who complete the trial without any protocol deviations) patients, will be performed using the statistical software package, IBM SPSS 27.0.DiscussionThis study will provide rigorous clinical evidence evaluating the efficacy and safety of using A&AA as a smoking cessation therapy.Trial registrationChinese Clinical Trial Registry (Registration number: ChiCTR1900028371).

Summary: Background: Multiple myeloma (MM) is still an incurable malignancy of plasma cells. Proteasome inhibitors (PIs) work as the backbone agent and have greatly improved the outcome in majority of newly diagnosed patients with myeloma. However, drug resistance remains the major obstacle causing treatment failure in clinical practice. Here, we investigated the effects of Indirubin-3’-monoxime (I3MO), one of the derivatives of Indirubin, in the treatment of MM. Methods: MM patient primary samples and human cell lines were examined. I3MO effects on myeloma treatment and the underling molecular mechanisms were investigated via in vivo and in vitro study. Findings: Our results demonstrated the anti-MM activity of I3MO in both drug- sensitive and -resistance MM cells. I3MO sensitizes MM cells to bortezomib-induced apoptosis. Mechanistically, I3MO acts as a multifaceted regulator of cell death, which induced DNA damage, cell cycle arrest, and abrogates NF-κB activation. I3MO efficiently down-regulated USP7 expression, promoted NEK2 degradation, and suppressed NF-κB signaling in MM. Our study reported that I3MO directly bound with and caused the down-regulation of PA28γ (PSME3), and PA200 (PSME4), the proteasome activators. Knockdown of PSME3 or PSME4 caused the inhibition of proteasome capacity and the overload of paraprotein, which sensitizes MM cells to bortezomib-mediated growth arrest. Clinical data demonstrated that PSME3 and PSME4 are over-expressed in relapsed/refractory MM (RRMM) and associated with inferior outcome. Interpretation: Altogether, our study indicates that I3MO is agent triggering proteasome inhibition and represents a promising therapeutic strategy to improve patient outcome in MM. Fundings: A full list of funding can be found in the acknowledgements.

Human gut microbiota interfere with host development and aging. Bifidobacterium is a microbial genus found in the human digestive tract that has probiotic activities such as improving constipation and enhancing immunity. The species and numbers present change with age, but there has been limited research on probiotic gut microbiota at specific ages. This study analyzed the distribution of 610 bifidobacteria in subjects in several age groups (0−17, 18−65, and 66−108 y) using 486 fecal samples and determined the distribution of glycoside hydrolases based on genetic analysis of strains representing 85% of the Bifidobacterium species abundance in each age group. 6’-Sialyllactose is a major component of acidic breast milk oligosaccharides, which can promote human neurogenesis and bifidobacteria growth. Using genotypic and phenotypic association analysis, we investigated the utilization of 6’-sialyllactose by six B. bifidum strains isolated from subjects 0–17 and 18–65 y. A comparative genomic analysis of the six B. bifidum strains revealed differences in genomic features across age groups. Finally, the safety of these strains was evaluated by antibiotic gene and drug resistance phenotype analysis. Our results reveal that the distribution of glycoside hydrolase genes in B. bifidum varies with age, thus affecting the phenotypic results. This provides important insights for the design and application of probiotic products for different ages.

Abstract Anaemia is the most common complication of myeloma and is associated with worse clinical outcomes. Although marrow replacement with myeloma cells is widely considered a mechanistic rationale for anaemia, the exact process has not been fully understood. Our large cohort of 1363 myeloma patients had more than 50% of patients with moderate or severe anaemia at the time of diagnosis. Anaemia positively correlated with myeloma cell infiltration in the bone marrow (BM) and worse patient outcomes. The quantity and erythroid differentiation of HSPCs were affected by myeloma cell infiltration in the BM. The master regulators of erythropoiesis, GATA1 and KLF1, were obviously downregulated in myeloma HSPCs. However, the gene encoding the chemokine CCL3 showed significantly upregulated expression. Elevated CCL3 in the BM plasma of myeloma further inhibited the erythropoiesis of HSPCs via activation of CCL3/CCR1/p38 signalling and suppressed GATA1 expression. Treatment with a CCR1 antagonist effectively recovered GATA1 expression and rescued erythropoiesis in HSPCs. Myeloma cell infiltration causes elevated expression of CCL3 in BM, which suppresses the erythropoiesis of HSPCs and results in anaemia by downregulating the level of GATA1 in HSPCs. Thus, our study indicates that targeting CCL3 would be a potential strategy against anaemia and improve the survival of myeloma patients.

Tree improvement programs often focus on improving productivity-related traits; however, under present climate change scenarios, climate change-related (adaptive) traits should also be incorporated into such programs. Therefore, quantifying the genetic variation and correlations among productivity and adaptability traits, and the importance of genotype by environment interactions, including defense compounds involved in biotic and abiotic resistance, is essential for selecting parents for the production of resilient and sustainable forests. Here, we estimated quantitative genetic parameters for 15 growth, wood quality, drought resilience, and monoterpene traits for Picea glauca (Moench) Voss (white spruce). We sampled 1,540 trees from three open-pollinated progeny trials, genotyped with 467,224 SNP markers using genotyping-by-sequencing (GBS). We used the pedigree and SNP information to calculate, respectively, the average numerator and genomic relationship matrices, and univariate and multivariate individual-tree models to obtain estimates of (co)variance components. With few site-specific exceptions, all traits examined were under genetic control. Overall, higher heritability estimates were derived from the genomic- than their counterpart pedigree-based relationship matrix. Selection for height, generally, improved diameter and water use efficiency, but decreased wood density, microfibril angle, and drought resistance. Genome-based correlations between traits reaffirmed the pedigree-based correlations for most trait pairs. High and positive genetic correlations between sites were observed (average 0.68), except for those pairs involving the highest elevation, warmer, and moister site, specifically for growth and microfibril angle. These results illustrate the advantage of using genomic information jointly with productivity and adaptability traits, and defense compounds to enhance tree breeding selection for changing climate.

Abstract Background There are still a large variety of microorganisms among aquatic animals, especially probiotic lactic acid bacteria in cold water fishes at high latitudes have not been fully developed. Hence, the present study aims to evaluate the probiotic potential of cold-adapted Lactobacillus strains isolated from the intestinal tract of cold water fishes (Xinjiang) and select candidates to be used as new food preservative agents and/or probiotic additives in feeding of aquaculture. Results A total of 43 Lactobacillus spp. were isolated from 16 kinds of intestinal tract of cold-water fishes. They were characterized by phenotypic methods, identified using Rep-PCR and 16S rRNA gene sequencing as four species: Lactobacillus sakei (22 isolates), Lactobacillus plantarum (16 isolates), Lactobacillus casei (4 isolates) and Lactobacillus paracasei (1 isolate). The in vitro tests included survival in low pH and bile, antimicrobial activity (against Escherichia coli, Salmonella enterica subsp. enterica serovar Typhimurium, Salmonella enterica subsp. enterica, Listeria monocytogenes, and Listeria innocua), resistance to 15 antibiotics and hemolytic tests. Among all 43 lactobacilli isolates, the 22 isolates showed a wide range of antimicrobial activity against 6 different pathogenic strains. There were twenty isolates growing at optimal temperature ranging 16~20 °C, which were initially considered to be cold-adapted strains. Two (2) Lb. sakei strains and 2 Lb. plantarum strains demonstrated the highest survivability after 4 h of exposure at pH 2.0. Most of the tested strains cannot be cultured after exposed into 0.5% bile solution for 4 h, while 2 Lb. plantarum strains (E-HLM-3, CQ-CGC-2) and 1 Lb. sakei strain M-DGM-2 survived even at 2% bile concentration. In addition, the safety assessment showed that 22 strains without any detectable hemolytic activity and resistant to glycopeptides (vancomycin, teicoplanin), levofloxacin, aztreonam, amikacin and oxacillin, while all the studied lactobacilli showed sensitivity to or semi-tolerant to other antibiotics. Conclusions Based on all the experiments, 3 strains, including E-HLM-3, CQ-CGC-2, and M-DGM-2 might be a candidate of choice for using in the food preservative agents and/or probiotic additives in feeding of aquaculture.

Objectives: Opioid dependence has been a threat to public health for hundreds of years. With the increasing number of studies on acupuncture-related therapies for opioid dependence patients receiving methadone maintenance treatment (MMT), its effect of acupuncture therapy in treating MMT patients remains controversial. Therefore, we conducted a multiple-treatments meta-analysis, and incorporated both direct and indirect comparisons, in order to discover the most effective treatment for opioid dependence patients receiving MMT.Methods: Five English databases and three Chinese databases were searched from its inception to August 20, 2020, in order to compare the effects of acupuncture-related therapies and MMT, which was summarized as Western medicine (WM) in the following texts. The quality of studies was assessed according to Cochrane's risk of bias tool 5.1.0, and a pair-wise meta-analysis, cumulative meta-analysis, and the network meta-analysis was performed using the R software (Version 3.6.1) and STATA (Version 14.0). The primary outcome was the effective rate, which was calculated by the ratio of detoxifying patients to the total. The secondary outcome was the Modified Himmelsbach Opiate Withdrawal Scale (MHOWS).Results: A total of 20 trials were included, which consisted of comparisons among WM, traditional Chinese medicine (TCM), and the four types of acupuncture, namely, manual acupuncture (MA), electro-acupuncture (EA), auricular acupuncture (AA), and transcutaneous electrical acupoint stimulation (TEAS). Though none of the trials were at low risk of bias. In the pair-wise meta-analysis, no statistically significant differences were observed in terms of the effective rate. Furthermore, MA was more efficacious than WM, EA, and TEAS in MHOWS, with mean differences (MDs) of (−8.59, 95% CI: −15.96 to −1.23, P < 0.01), (−6.15, 95% CI: −9.45 to −2.85, P < 0.05), and (−10.44, 95% CI: −16.11 to −4.77, P < 0.05), respectively. In the network meta-analysis, MA was more effective than WM (RR: 1.40, 95% CI: 1.05 to 1.99) on the effective rate, and (MD: −5.74, 95% CI: −11.60 to −0.10) on MHOWS. TEAS was more effective than WM (MD: −15.34, 95% CI: −27.34 to −3.46) on MHOWS. Synthetically, MA had the highest probability to rank first in treating opioid dependence.Conclusions: The existing evidence shows that acupuncture related-therapies may effectively be used for treating patients receiving MMT, and that manual acupuncture may be the best choice for opioid dependence among all kinds of acupuncture-related therapies. Nevertheless, reducing the relapse and promoting the recovery of opioid dependence need more efforts from not only the medical industry but also government support, security system, and educational popularization. To strengthen the assurance of acupuncture-related therapies in the treatment of opioid dependence, we expected that clinical trials with high quality would be conducted, to provide more confident evidence.

Myeloma bone disease (MBD), caused by the inhibition of osteoblast activity and the activation of osteoclast in the bone marrow environment, is the most frequent and life-threatening complication in multiple myeloma (MM) patients. Bortezomib (Bzb) was shown to promote MM-derived mesenchymal stem cells (MM-MSCs) differentiation to osteoblast in vitro and in animal models, promoting the bone formation and regeneration, may be mediated via β-catenin/T-cell factor (TCF) pathway. Further defining molecular mechanism of Bzb-enhanced bone formation in MM will be beneficial for the treatment of myeloma patients. The present study has identified for the first time four and a half LIM domains protein 2 (FHL2), a tissue-specific coregulator that interacts with many osteogenic marker molecules, as a therapeutic target to ameliorate MM bone disease. First, increased messenger RNA (mRNA) and protein levels of FHL2, and the mRNA level of main osteoblast markers (including Runx2, ALP, and Col1A1), were found in MM-patients-derived MSCs after Bzb treatment. FHL2 KD with short hairpin RNA (shRNA) reduced the expression of osteoblast marker genes and blocked the osteogenic differentiation of MM-MSCs regardless of the presence or absence of Bzb, implying that FHL2 is an important activator of the osteogenic differentiation of human MSCs under a proteasome inhibition condition. Molecular analysis showed that the enhanced expression of FHL2 was associated with the Bzb-induced upregulation of p53. No significant change at protein level of total β-catenin was observed with or without Bzb treatment. However, it was mostly enriched to nuclei in MSCs after Bzb treatment. Moreover, β-catenin was restricted to the perinuclear region in FHL2 KD cells. These data provide evidence that FHL2 is essential for promoting β-catenin nuclear enrichment in MM-MSCs. In conclusion, FHL2 is critical for Bzb-induced osteoblast differentiation of MM-MSCs and promotes the osteogenesis, through p53 signaling and β-catenin activation. Targeting FHL2 in MM may provide a new therapeutic strategy for treating MBD.

Objective: From the health care and societal perspectives, this study aimed to evaluate the clinical and economic effects of acupuncture as an adjunctive therapy for patients receiving methadone maintenance treatment (MMT).Methods: We conducted a parallel-arm RCT in China in 2019. Patients were included who met the diagnostic criteria and receive MMT for more than 30 days. Patients were randomly assigned to the exposed group (acupuncture plus MMT) or control group (MMT) at a 1:1 ratio. Daily methadone dosage, drug cravings using the VAS score, and insomnia using the Pittsburgh Sleep Quality Index (PSQI) were chosen as the effectiveness indexes, and the quality-adjusted life years (QALYs) was chosen as the utility index.Results: Overall, 123 patients were included. The exposed group was significantly (P < 0.05) better than the control group in the improvement of daily methadone dosage (17.68 vs. 1.07), VAS (38.27 vs. 2.64), and PSQI (2.18 vs. 0.30). The QALY was 0.0784 (95%CI: 0.0761–0.0808) for the exposed group and 0.0762 (95%CI: 0.0738–0.0787) for the control group. The total cost of the exposed group (2869.50 CNY) was higher than the control group (2186.04 CNY). The ICER of daily methadone dosage (41.15), VAS (17.86), and PSQI (313.51) were shown to be economically efficient. While ICUR (310,663.64 CNY/QYLY) was higher than the cost suggested by WHO.Conclusion: Acupuncture as an adjuvant therapy for MMT patients realizes its cost-effectiveness by reducing the dosage of methadone, improving drug cravings, and alleviating insomnia. It helps to improve quality of life, but since its cost exceeds what society is willing to pay, further study is needed.

Background: Since the outbreak of coronavirus disease (COVID-19), acupuncture has been widely used in the treatment of COVID-19. The research community has responded rapidly and has already published many research articles about this topic. Methods: We searched PubMed, Embase, Cochrane Library as well as CNKI, Wanfang and VIP from January 1, 2020 to July 31, 2021. The dates of publication, language of publication, methodological characteristics and the key findings were analyzed separately. The data are presented as bar graphs, structured tables and figures. Results: In this scoping review, 16 research articles were included: 7 case reports, 6 observational studies, 1 review, 1 RCT and 1 nonrandomized clinical trial. The majority of the articles (81.3%) were published by Chinese scholars, 12.5% articles were by scholars in the United States, and 6.3% articles were by scholars in Iran. The included studies reported that acupuncture could alleviate the symptoms of COVID-19 patients, shorten their hospitalization days, and is effective for the elderly. There were no side effects reported. The most frequent acupoints used were LI4, PC6, ST36 and KI3. They reported many obstacles in implementing acupuncture therapy for treating COVID-19 patients. Conclusion: Acupuncture has a good effect for the treatment of COVID-19, but high-quality evidence support is still lacking. Coupled with the difficulties that acupuncturists experienced during the process of treatment, the promotion of acupuncture treatment for COVID-19 faces many obstacles.

Distribution of hydrological parameters is varied under contrasting meteorological conditions. However, how to determine the most suitable parameters on a predefined meteorological condition is challenging. To address this issue, a hydrological prediction method based on meteorological classification is established, which is conducted by using the standardized runoff index (SRI) value to identify three categories, i.e., the dry, normal and wet years. Three different simulation schemes are then adopted for these categories. In each category, two years hydrological data with similar SRI values are divided into a set; then, one-year data are used as the calibration period while the other year is for testing. The Génie Rural à 4 paramètres Journalier (GR4J) rainfall-runoff model, with four parameters x1, x2, x3 and x4, was selected as an experimental model. The generalized likelihood uncertainty estimation (GLUE) method is used to avoid parameter equifinality. Three basins in Australia were used as case studies. As expected, the results show that the distribution of the four parameters of GR4J model is significantly different under varied meteorological conditions. The prediction efficiency in the testing period based on meteorological classification is greater than that of the traditional model under all meteorological conditions. It is indicated that the rainfall-runoff model should be calibrated with a similar SRI year rather than all years. This study provides a new method to improve efficiency of hydrological prediction for the basin.

N1-methylnicotinamide (MNAM), a product of methylation of nicotinamide through nicotinamide N-methyltransferase, displays antidiabetic effects in male rodents. This study aimed to evaluate the ameliorative potential of MNAM on glucose metabolism in a gestational diabetes mellitus (GDM) model. C57BL/6N mice were fed with a high-fat diet (HFD) for 6 weeks before pregnancy and throughout gestation to establish the GDM model. Pregnant mice were treated with 0.3% or 1% MNAM during gestation. MNAM supplementation in CHOW diet and HFD both impaired glucose tolerance at gestational day 14.5 without changes in insulin tolerance. However, MNAM supplementation reduced hepatic lipid accumulation as well as mass and inflammation in visceral adipose tissue. MNAM treatment decreased GLUT4 mRNA and protein expression in skeletal muscle, where NAD+ salvage synthesis and antioxidant defenses were dampened. The NAD+/sirtuin system was enhanced in liver, which subsequently boosted hepatic gluconeogenesis. GLUT1 protein was diminished in placenta by MNAM. In addition, weight of placenta, fetus weight, and litter size were not affected by MNAM treatment. The decreased GLUT4 in skeletal muscle, boosted hepatic gluconeogenesis and dampened GLUT1 in placenta jointly contribute to the impairment of glucose tolerance tests by MNAM. Our data provide evidence for the careful usage of MNAM in treatment of GDM. [ABSTRACT FROM AUTHOR]