Multidomain interventions for non-pharmacological enhancement (MINE) program in Chinese older adults with mild cognitive impairment: a multicenter randomized controlled trial protocol.

BACKGROUND: Dementia is characterized by progressive neurodegeneration and therefore early intervention could have the best chance of preserving brain health. There are significant differences in health awareness, living customs, and daily behaviors among Chinese older adults compared to Europeans and Americans. Because the synergistic benefits of multidomain non-pharmacological interventions are consistent with the multifactorial pathogenicity of MCI, such interventions are more appealing, easier to adhere to, and more relevant to daily life than single-mode interventions. One of the aims of this study is to verify the effect of multidomain intervention strategies for MCI patients based on Chinese population characteristics, and the other is to establish a biobank and image database to investigate the pathogenesis and pathways of cognitive impairment. METHODS: Our study was designed as a national multicenter, community-based randomized controlled trial (RCT). Twelve medical institutions in ten Chinese cities will participate in our study from 2020 to 2024, and 1080 community residents aged 50 and above will be enrolled as participants. Each sub-center will be responsible for 90 participants (30 people per community) across three communities (non-contact control group, health education group, and multidomain intervention group). The community will be the basic unit of the present study, and all participants in each community will receive the same intervention/control measure. Three working groups are set up in each sub-center to manage the three communities independently to minimize interference at the implementation level between the groups. The multidomain intervention group will receive integrated interventions including exercise, nutrition, sleep, health education and mindfulness meditation. All data generated by the research will be analyzed and processed by statistical software (such as SPSS 21.0, Python 3.0, etc.), and part of the research data will be displayed in the form of graphs and tables. DISCUSSION: In order to achieve a high-quality community intervention study, it is crucial to have a well-designed experimental protocol that follows rigorous scientific methodology. In addition, effective management of quality control measures and monitoring compliance throughout the study process are essential components. This study provides a detailed discussion of stakeholder compliance, research quality control, potential harm and mitigation, auditing, and future plans in order to better address research issues. TRIAL REGISTRATION: ChiCTR2000035012 (July 27, 2020).

Associations of geriatric nutrition risk index and other nutritional risk-related indexes with sarcopenia presence and their value in sarcopenia diagnosis.

OBJECTIVE: Standard modalities recommended for sarcopenia diagnosis may be unavailable in primary care settings. We aimed to comprehensively evaluate and compare associations of some better popularized nutritional risk-related indexes with sarcopenia presence and their value in sarcopenia diagnosis in community-dwelling middle-aged and elderly adults, including geriatric nutrition risk index (GNRI), albumin (ALB), calf circumference (CC), mid-arm circumference (MAC), triceps skinfold thickness (TST) and body mass index (BMI). METHODS: Based on the West China Health and Aging Trend study, the current study included participants aged 50 or older who were recruited in 2018. Sarcopenia-related assessment and diagnosis were in line with Asian Working Group for Sarcopenia 2019. For each single index, we assessed its association with sarcopenia presence by univariate and multivariate logistic regression analysis; we also computed diagnostic measures including the area under the receiver operating characteristic curve (AUC) and sensitivity, specificity, accuracy at the optimal cut-off value determined according to Youden's index. RESULTS: A total of 3829 subjects were included, consisting of 516 and 3313 subjects in the sarcopenia and non-sarcopenia groups, respectively. Regarding the risk for sarcopenia presence, the fully adjusted odds ratios of GNRI, ALB, CC, MAC, TST and BMI per standard deviation decrease were 2.95 (95% CI 2.51-3.47, P < 0.001), 1.01 (95% CI 0.90-1.15, P = 0.816), 4.56 (95% CI 3.82-5.44, P < 0.001), 4.24 (95% CI 3.56-5.05, P < 0.001), 1.67 (95% CI 1.92-1.45, P < 0.001) and 4.09 (95% CI 3.41-4.91, P < 0.001), respectively. Regarding the value in sarcopenia diagnosis in the entire study population, their AUCs could be ordered as MAC (0.85, 95% CI 0.83-0.86) > GNRI (0.80, 95% CI 0.78-0.82), CC (0.83, 95% CI 0.81-0.85), BMI (0.81, 95% CI 0.79-0.83) > TST (0.72, 95% CI 0.70-0.74) > ALB (0.62, 95% CI 0.60-0.65). At the relevant optimal cut-off values, the sensitivity was the highest for CC (0.83, 95% CI 0.80-0.87) and MAC (0.80, 95% CI 0.77-0.84), while GNRI showed the highest specificity (0.79, 95% CI 0.78-0.81) and accuracy (0.78, 95% 0.76-0.79). CONCLUSION: Overall diagnostic performance was the best for MAC, followed by GNRI, CC, BMI, and the worst for TST, ALB in distinguishing sarcopenia from non-sarcopenia in middle-aged and elderly adults in community-based settings. CC or MAC might do better in reducing missed diagnosis, while GNRI was superior in reducing misdiagnosis.

Accelerated progression of Hodgkin's-like lymphomas in golli deficient SJL mice.

Spontaneously occurring lymphomas in SJL mice have many pathological features similar to Hodgkin's lymphoma in humans. The malignant growth of the tumor cells is dependent on the support of host FoxP3(+)CD4(+) regulatory T cells (Tregs). In this study, we report that the ablation of golli protein, a negative regulator of CRAC (calcium release activated calcium) channel, in SJL mice results in an accelerated progression of Hodgkin's-like lymphoma which is accompanied by a facilitated conversion of FoxP3(+) Treg cells. Our results suggest that golli protein might affect the progression of Hodgkin's-like lymphomas through regulating the induction of Treg cells.

Clinical evaluation of the reference intervals for diabetes in Chinese geriatric population: a cross-sectional cohort study protocol.

INTRODUCTION: Diabetes mellitus (DM) is an important health issue that affects the ageing population. China has the largest geriatric population and the largest number of diabetes cases in the world. This poses a significant challenge for healthcare providers and policymakers. Haemoglobin A1C (HbA1c), which is one of the diagnostic criteria for diabetes, is affected by many factors such as pregnancy, age, race and anaemia. Glycated albumin (GA) is not influenced by factors that affect HbA1c concentrations, although it has been used in the diagnosis of diabetes in a few people. The aim of this study protocol is to determine reference intervals (RIs) of HbA1c and GA for the diagnosis of older adults with diabetes in China and to assess the optimal cut-off values for these parameters from a health economic perspective. METHODS AND ANALYSIS: This cross-sectional survey study will recruit 1278 community-dwelling older adults aged 60-89 in Chengdu City. The data collection process will involve a questionnaire survey, a comprehensive physical examination and the collection of blood samples for laboratory testing. Data analyses will be conducted on the pooled sample and stratified by gender, age or other demographic features if necessary. Rates will be compared using the χ2 test or Fisher test and receiver operating characteristic (ROC) curves will be used to identify the most effective threshold values for HbA1c and GA for diagnosing diabetes among older adults in China. ETHICS AND DISSEMINATION: The study protocol was approved by the ethics review board of the Bioethics Subcommittee of West China Hospital, Sichuan University (Approval No. 1705 in 2022). The study's results will be disseminated through peer-reviewed journals and scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300070831.

The contribution of probiotics for the double-edge effect of cefazolin on postoperative neurocognitive disorders by rebalancing the gut microbiota.

Introduction: Emerging data suggest that perioperative gut dysbiosis is prevalent and may be associated with postoperative neurocognitive disorders (PND). Antibiotics and probiotics are key factors influencing the microbiota. Many antibiotics have anti-microorganisms and direct anti-inflammatory properties, which may have cognitive repercussions. NLRP3 inflammasome activation has been reported to be involved with cognitive deficits. This study aimed to determine the effect and mechanism of probiotics on neurocognitive problems associated with perioperative gut dysbiosis by the NLRP3 pathway. Methods: In a randomized, controlled trial, adult male Kunming mice undergoing surgery were administered cefazolin, FOS + probiotics, CY-09, or a placebo in four distinct experimental cohorts. Fear conditioning (FC) tests evaluate learning and memory. Following FC tests to evaluate inflammatory response (IR) and the permeability of barrier systems, the hippocampus and colon were extracted, and feces were collected for 16 s rRNA. Results: One week after surgery, surgery/anesthesia decreased the frozen behavior. Cefazolin attenuated this declination but aggravated postoperative freezing behavior 3 weeks after surgery. Probiotics ameliorated surgery/anesthesia-induced memory deficits and perioperative cefazolin-induced postoperative memory deficits 3 weeks after surgery. NLRP3, caspase-1, Interleukin-1ß (IL-1ß), and Interleukin-18 (IL-18) levels were increased 1 week after the hippocampus and colon surgery, which were attenuated by CY-09 and probiotics, respectively. Discussion: Probiotics could correct dysbacteria and IR caused by surgery/anesthesia stress and cefazolin alone. These findings imply that probiotics are an efficient and effective way of maintaining the balance of gut microbiota, which may reduce NLRP3-related inflammation and alleviate PND.

Spiroplasma spp. biofilm formation is instrumental for their role in the pathogenesis of plant, insect and animal diseases.

Spiroplasma spp. are important phyto and insect pathogens, and candidate causal agent/s of transmissible spongiform encephalopathies (TSE) in man and animals. These filterable wall-less bacteria are widely distributed in nature with an unspecified environmental reservoir. In this study we showed by scanning electron microscopy that spiroplasma form biofilm on an assortment of hard surfaces including mica, nickel and stainless steel. Spiroplasma were stuck to the surfaces by fibrillar threads consistent with curli fibers (an amyloid protein found in bacterial biofilms). After a lengthy time in cultures (6 weeks), spiroplasma in biofilm bound to mica disks lost their spiral shapes and formed coccoid forms interconnected by long (>2 µm) branched membranous nanotubules, therein representing direct conjugate connections between the cells. The affinity of spiroplasma biofilms for mica and nickel, and the membrane communications suggest that soil could be a reservoir for these bacteria. The persistence of clay bound spiroplasma in soil could serve as the mechanism of lateral spread of TSEs by ingestion of soil by ruminants. Spiroplasma binding to stainless steel wire supports bacterial contamination of surgical instruments following surgery on dementia patients as a mechanism of iatrogenic transmission of TSEs, especially with resistance of spiroplasma in biofilms to drying or exposure to 50% glutaraldehyde. The discovery of biofilm formation by spiroplasma addresses questions regarding environmental persistence of these organisms in nature and suggests novel mechanisms of intercellular communication and transmission.

Centenarians Alleviate Inflammaging by Changing the Ratio and Secretory Phenotypes of T Helper 17 and Regulatory T Cells.

The immune system of centenarians remains active and young to prevent cancer and infections. Aging is associated with inflammaging, a persistent low-grade inflammatory state in which CD4+ T cells play a role. However, there are few studies that have been done on the CD4+ T cell subsets in centenarians. Herein, the changes in CD4+ T cell subsets were investigated in centenarians. It was found that with aging, the old adults had higher levels of proinflammatory cytokines and lower levels of anti-inflammatory cytokines in plasma. The levels of CRP, IL-12, TNF-α, IFN-γ, IL-6 and IL-10 were further increased in centenarians compared to old adults. While the levels of IL-17A, IL-1ß, IL-23 and TGF-ß in centenarians were closer to those in young adults. The total CD4+, CD8+, Th17 and Treg cells from peripheral blood mononuclear cells (PBMCs) were similar among the three groups. It was observed that the ratio of Th17/Treg cells was elevated in old adults compared to young adults. The ratio was not further elevated in centenarians but rather decreased. In addition, the ex vivo PBMCs differentiation assay showed that increased Th17 cells in centenarians tended to secrete fewer proinflammatory cytokines, while decreased Treg cells in centenarians were prone to secrete more anti-inflammatory cytokines. These observations suggested centenarians alleviated inflammaging by decreasing the ratio of Th17/Treg cells and changing them into anti-inflammatory secretory phenotypes, which provided a novel mechanism for anti-aging research.

Natural population cohort study on long-lived adults: West China longevity and ageing procedure (WCLAP).

PURPOSE: The West China longevity and ageing procedure (WCLAP) cohort study aims to provide guidance for older adults in western China with the aim of improving quality of life, reducing the burden of family care, summarising the characteristics of longevity lifestyles, building a Chinese-longevity-population biobank and exploring the mechanisms underlying population ageing. PARTICIPANTS: Since the establishment of the WCLAP research baseline in 2018, a population of 1537 adults aged 80 years and above, living in the community, have been enrolled in the programme as research participants. Of these, 231 are aged 100 years and above. Participants are followed up every year. FINDING TO DATA: WCLAP data are collected in five hospital research subcentres strategically located adjacent to the national 'Longevity Townships' of Chengdu Ziyang, Leshan, Yibin and Pengshan. Data collection included a comprehensive assessment of the participant's health (including physical, psychological, social and common chronic disease assessments), instrumental tests (body composition and muscle percentage) and the collection of biomedical-biobank samples (include blood, urine, faeces, hair and urine). FUTURE PLANS: Through the annual cohort follow-up, survival-related information is collected at a group level. Analysis of biological samples facilitates biological characterisation at the microscopic level through proteomics, metabolomics, genomics and other techniques. Baseline data, group-level follow-up data and microbiological examination data are integrated together to provide an evaluation tool, exploring sarcopenia, disability, dementia, caregiver burden, ageing biomarkers and other influencing factors. TRIAL REGISTRATION NUMBERS: 2018-463; ChiCTR1900020754.

Efficiency and safety of ablation procedure for the treatment of atrial fibrillation in valve surgery: A PRISMA-compliant cumulative systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation is the main complication of patients who suffer from valvular heart disease (VHD), which may lead to an increased susceptibility to ventricular tachycardia, atrial dysfunction, heart failure, and stroke. Therefore, seeking a safe and effective therapy is crucial in prolonging the lives of patients with VHD and improving their quality of life. METHODS: Our target database included PubMed, Web of Science, Embase, and Cochrane Library, from which published articles were retrieved from inception to June 2020. We retrieved all randomized controlled trials (RCTs) that compared patients undergoing valve surgery with (VSA) or without ablation (VS) procedure. Studies to be included were screened and data extraction was performed independently by 2 investigators. The Cochrane risk-of-bias table was used to evaluate the methodological quality of the included RCTs. The mean difference (MD) with 95% confidence interval (CI) and relative risk (RR) ratio was calculated to analyze the data. Heterogeneity was evaluated using I2 and chi-square tests. Egger test and the trim and fill analysis were used to further determine publication bias. RESULTS: Fourteen RCTs that included 1376 patients were eventually selected for this meta-analysis. Surgical ablation was found to be effective in restoring sinus rhythm in valvular surgery patients at discharge (RR 2.91, 95% CI [1.17, 7.20], I2 97%, P = .02), 3 to 6 months (RR 2.85, 95% CI [2.27, 3.58], I2 49%, P < .00001), 12 months, and more than 1 year after surgery (RR 3.54, 95% CI [2.78, 4.51], I2 27%, P < .00001). All-cause mortality (RR 0.98, 95% CI [0.64, 1.51], I2 0%, P = .94) and stroke (RR 1.29, 95% CI [0.70, 2.39], I2 0%, P = .57) were similar in the VSA and VS groups. Compared with VS, VSA prolonged cardiopulmonary bypass time (MD 30.44, 95% CI [17.55, 43.33], I2 88%, P < .00001) and aortic cross-clamping time (MD 19.57, 95% CI [11.10, 28.03], I2 89%, P < .00001). No significant differences were found between groups with respect to the risk of bleeding (RR 0.64, 95% CI [0.37, 1.12], I2 0%, P = .12), heart failure (RR 1.11, 95% CI [0.63, 1.93], I2 0%, P = .72), and low cardiac output syndrome (RR 1.41, 95% CI [0.57, 3.46], I2 18%, P = .46). However, the demand for implantation of a permanent pacemaker was significantly higher in the VSA group (RR 1.84, 95% CI [1.15, 2.95], I2 0%, P = .01). CONCLUSION: Although we found high heterogeneity in the restoration of sinus rhythm at discharge, we assume that the comparison is valid at this time, given the current state in the operating room. This study provides evidence of the efficacy and security of concomitant ablation intervention for patients with VHD and atrial fibrillation. Surgical ablation would increase the safety of implantation of a permanent pacemaker in the population that underwent valve surgery.

The 100 top-cited studies on postoperative hyperalgesia in the last 30 years: a bibliometric analysis.

BACKGROUND: In recent years, the issue of postoperative pain has raised wide concern in the medical community. Postoperative hyperalgesia (POH), as the primary etiology of pain, has been extensively studied and numerous articles have been published on this topic; however, no comprehensive bibliometric review of POH publications has been conducted. Thus, we aimed to examine the 100 top-cited reports on POH and summarize their key characteristics. METHODS: Published studies on POH were retrieved from the Web of Science Core Collection (WoSCC) using the search terms "postoperative hyperalgesia". All papers published since 1980 were searched. The search results were sorted by the frequency of the total citations, and 2 reviewers independently skimmed the abstracts and full texts to identify the 100 top-cited reports. After the 100 top-cited papers were identified, the following data were extracted by the two reviewers: the title, surname(s) of the author(s), name of the first author, publication year, country of origin, article type, institutional affiliations, keywords, source journal, and impact factor (IF) of the journal. RESULTS: The initial search returned 1,747 papers, published in 466 journals that originated from 1,679 institutions in 48 countries. The 100 top-cited reports received 21,454 citations. The USA was the most cited and most productive country, contributing nearly half of the 100 top-cited papers. The numbers of studies on POH have trended upward and continue to increase each year. CONCLUSIONS: An analysis of the 100 top-cited studies on POH provided a better guidance for ongoing researches. The prominent keywords "opioid-induced hyperalgesia", especially "remifentanil", is still on top of POH research area. Nevertheless, the mechanism of POH is intricate and unclear, which is crucial to conduct further studies and find some new interventions.

Novel Spiroplasma Spp. Cultured From Brains and Lymph Nodes From Ruminants Affected With Transmissible Spongiform Encephalopathy.

Spiroplasma spp., tiny filterable wall-less bacteria, are consistently associated with the transmissible spongiform encephalopathies (TSE). Spiral forms have been transiently isolated from TSE-affected brain tissues in SP4 growth media designed for isolation of Spiroplasma spp., but the isolate could not be propagated in SP4 media. A bacterium must grow in vitro in cell-free cultures to allow full characterization of a suspect pathogen. Here, a novel Spiroplasma sp. was isolated from scrapie- and chronic wasting disease (CWD)-affected brains and lymph nodes. Filtrates of tissue homogenates inoculated into Brucella media incubated for 14 days at 35 °C resulted in high titers of spiroplasma as shown by dark-field microscopy. A drop assay of infected media on Bacto Schaedler agar showed spiroplasma isolates forming unique subsurface colonies after 21 days incubation. Spiroplasma coils, coccoid forms and clumps of entwined spiroplasma filaments were seen on the agar by scanning electron microscopy. Since Brucella media has a sodium bisulfite additive that lowers oxygen tension, TSE spiroplasma growth requires media with low oxygen tension. Brucella media allows for isolation and propagation of spiroplasma from TSE-affected tissues, which will lead to complete characterization of this TSE pathogen and determine its role as a candidate causative agent of TSE.

CD4+ T cell acquisition of the bystander pMHC I colocalizing in the same immunological synapse comprising pMHC II and costimulatory CD40, CD54, CD80, OX40L, and 41BBL.

We previously showed that CD4+ T cells acquired peptide/major histocompatibility complex (pMHC) I and costimulatory molecules by dendritic cell (DC) activation. However, the molecular mechanism for pMHC I acquisition is unclear. In this study, by using a panel of engineered DC2.4 cells or incubation of these cells with Con A-stimulated CD4+ T cells, we conducted capping and synapse formation assay and examined them by confocal fluorescence microscopy. We demonstrated that (i) CD54 and CD80 colocalized with pMHC I/II in the same lipid rafts, whereas CD40, OX40L, and 41BBL localized in the lipid rafts but separately from pMHC I/II, and (ii) MHC I/II colocalized with the costimulatory molecules in the same synapse formed between a DC and a CD4+ T cell, leading to expression of the acquired bystander pMHC I on CD4+ T cells via internalization/recycling pathway. These results provide some useful information in composition and dynamics of immunological synapses.

Bidirectional membrane molecule transfer between dendritic and T cells.

The acquisition of dendritic cell (DC) molecules by T cells has been previously reported. However, it remains unclear whether the transfer is only mono- or bidirectional. In this study, we incubated CMFDA-labeled ovalbumin (OVA)-pulsed DC2.4 (DC2.4(OVA)) cells with Dil-labeled OT II CD4(+) T cells and analyzed the potential bidirectional molecule transfer. We also assessed the distribution of internalized membrane using two engineered DC2.4/Ia(b)GFP and MF4/TCRCFP DC lines. Our findings showed that membrane molecule transfer is bidirectional. CD4(+) T cells acquired Ia(b), CD11c, CD40, and CD80 from DC2.4(OVA) cells, and conversely DC2.4(OVA) cells took up CD4, CD25, CD69, and T cell receptor from T cells. The internalized molecules acquired by T cells and DCs mostly localized in endosomes and lysosomes, respectively. Taken together, this study demonstrated a novel phenomenon of bidirectional membrane molecule transfer between DCs and T cells.

Novel exosome-targeted CD4+ T cell vaccine counteracting CD4+25+ regulatory T cell-mediated immune suppression and stimulating efficient central memory CD8+ CTL responses.

T cell-to-T cell Ag presentation is increasingly attracting attention. In this study, we demonstrated that active CD4+ T (aT) cells with uptake of OVA-pulsed dendritic cell-derived exosome (EXO(OVA)) express exosomal peptide/MHC class I and costimulatory molecules. These EXO(OVA)-uptaken (targeted) CD4+ aT cells can stimulate CD8+ T cell proliferation and differentiation into central memory CD8+ CTLs and induce more efficient in vivo antitumor immunity and long-term CD8+ T cell memory responses than OVA-pulsed dendritic cells. They can also counteract CD4+25+ regulatory T cell-mediated suppression of in vitro CD8+ T cell proliferation and in vivo CD8+ CTL responses and antitumor immunity. We further elucidate that the EXO(OVA)-uptaken (targeted)CD4+ aT cell's stimulatory effect is mediated via its IL-2 secretion and acquired exosomal CD80 costimulation and is specifically delivered to CD8+ T cells in vivo via acquired exosomal peptide/MHC class I complexes. Therefore, EXO-targeted active CD4+ T cell vaccine may represent a novel and highly effective vaccine strategy for inducing immune responses against not only tumors, but also other infectious diseases.

Enhanced antitumor immunity derived from a novel vaccine of fusion hybrid between dendritic and engineered myeloma cells.

AIM: Dendritic cell-tumor cell fusion hybrid vaccines which facilitate antigen presentation represent a new powerful strategy in cancer immunotherapy. The clinical frequency of objective responses to the conventional fusion hybrid vaccines is still quite low, indicating that the current conventional protocol of simply fusing dendritic cells (DCs) and tumor cells needs further improvement to enhance its antitumor efficiency. METHODS: In the present study, we generated a novel fusion hybrid DC/J558(CD40L) by fusing DCs and an engineered J558(CD40L) myeloma cells expressing CD40 ligand (CD40L) molecule using polyethylene glycol (PEG). The fusion efficiency was approximately 20%. We investigated the antitumor immunity derived from vaccination of the fusion hybrid DC/J558(CD40L). RESULTS: Our results showed that vaccination of mice with DC/J558(CD40L) hybrids induced more efficient cytotoxic T lymphocyte (CTL) responses and protective immunity against J558 tumor cells, than that of the conventional fusion hybrid DC/J558 from the fusion of DCs and J558 tumor cells. The antitumor immunity derived from vaccination of DC/J558(CD40L) was mainly mediated by CD4(+) and CD(8+)cT cells, but not natural killer (NK) cells. CONCLUSION: Therefore, this novel fusion hybrid vaccine which combines gene-modified tumor and DC vaccines may be an attractive strategy for cancer immunotherapy.