Exploring the glycolytic cross-talk genes between inflammatory bowel disease and colorectal cancer.

Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer (CRC). Glycolysis is involved in the development of both IBD and CRC. However, the mechanisms and outcomes of glycolysis shared between IBD and CRC remain unclear. This study aimed to explore the glycolytic cross-talk genes between IBD and CRC integrating bioinformatics and machine learning. With WGCNA, LASSO, COX, and SVM-RFE algorithms, P4HA1 and PMM2 were identified as glycolytic cross-talk genes. The independent risk signature of P4HA1 and PMM2 was constructed to predict the overall survival rate of patients with CRC. The risk signature correlated with clinical characteristics, prognosis, tumor microenvironment, immune checkpoint, mutants, cancer stemness, and chemotherapeutic drug sensitivity. CRC patients with high risk have increased microsatellite instability, tumor mutation burden. The nomogram integrating risk score, tumor stage, and age showed high accuracy for predicting overall survival rate. In addition, the diagnostic model for IBD based on P4HA1 and PMM2 showed excellent accuracy. Finally, immunohistochemistry results showed that P4HA1 and PMM2 were significantly upregulated in IBD and CRC. Our study reveals the presence of glycolytic cross-talk genes P4HA1 and PMM2 between IBD and CRC. This may prove to be beneficial in advancing research on the mechanism of development of IBD-associated CRC.

Association between systemic immune-inflammation index and chronic obstructive pulmonary disease: a population-based study.

BACKGROUND: The Systemic Immune-Inflammation Index (SII) is a quantitative measurement of the systemic immune-inflammatory response in the human body. The SII has been shown to have prognostic value in various clinical settings, including critical illness, sepsis, and cancer. Its role in chronic obstructive pulmonary disease (COPD) remains unclear and requires further investigation. METHODS: We analyzed demographic data from 16,636 participants in the National Health and Nutrition Examination Survey. Logistic regression analysis was performed to assess the correlation between COPD, lung function, chronic respiratory symptoms and SII. We used Cox proportional hazards (PH) model to analyze the relationship between SII and mortality in COPD patients and healthy individuals. We used propensity score matching (PSM) method to match the COPD population with similar baseline levels with the normal population to further analyze the correlation between SII and COPD. RESULTS: We recruited 16,636 participants, ages 40 and above, for the study. A multivariable logistic regression analysis revealed that a higher SII level was independently associated with an elevated likelihood of COPD (Odds Ratio (OR) = 1.449; 95% Confidence Interval (CI): 1.252-1.676, P < 0.0001) after controlling for all other factors. Results of subgroup analysis showed a significant positive correlation between SII and COPD in different age groups, gender, Body Mass Index, smoking status, and those with a history of hypertension. The SII index had positive correlation with COPD after PSM (OR = 1.673; 95%CI: 1.443-1.938). After full adjustment, an increase in the SII is associated with a higher all-cause mortality rate. The hazard ratio (HR) with a 95% CI in the general population, COPD patients, and healthy individuals are 1.161 (1.088, 1.239), 1.282 (1.060, 1.550), and 1.129 (1.055, 1.207), respectively. CONCLUSIONS: Higher SII levels are linked to higher prevalence of COPD. COPD patients with a higher SII levels have a higher risk of all-cause mortality. Additional large-scale, long-term studies are necessary to confirm these results.

Preprocedural Lp(a) level and ApoB/ApoA-Ι ratio and the risk for contrast-induced acute kidney injury in patients undergoing emergency PCI.

BACKGROUND: High serum Lipoprotein(a) (Lp(a)) level and Apolipoprotein B/Apolipoprotein AΙ (ApoB/ApoA-Ι) ratio are risk factors for cardiovascular disease and kidney disease and have been found to be correlated with the prevalence and prognosis of various kidney diseases. However, it is not clear whether the serum Lp(a) level and ApoB/ApoA-Ι ratio pre-PCI are correlated with the prevalence of contrast-induced acute kidney injury (CI-AKI). METHODS: A total of 931 participants undergoing emergency PCI from July 2018 to July 2020 were included. According to whether the serum creatinine concentration was higher than the baseline concentration (by ≥25% or ≥ 0.5 mg/dL) 48-72 h after contrast exposure, these participants were divided into a CI-AKI group (n = 174) and a non-CI-AKI group (n = 757). Serum Lp(a), ApoA-Ι and ApoB concentration were detected in the patients when they were admitted to hospital, and the ApoB/ApoA-Ι ratio was calculated. Logistic regression and restricted cubic spline analyses were used to explore the correlation between the Lp(a) concentration or the ApoB/ApoA-Ι ratio and the risk of CI-AKI. RESULTS: Among the 931 participants undergoing emergency PCI, 174 (18.69%) participants developed CI-AKI. Compared with the non-CI-AKI group, the Lp(a) level and ApoB/ApoA-Ι ratio pre-PCI in the CI-AKI group were significantly higher (P < 0.05). The incidence of CI-AKI was positively associated with the serum Lp(a) level and ApoB/ApoA-Ι ratio pre-PCI in each logistic regression model (P < 0.05). After adjusting for all the risk factors included in this study, restricted cubic spline analyses found that the Lp(a) level and the ApoB/ApoA-Ι ratio before PCI, within certain ranges, were positively associated with the prevalence of CI-AKI. CONCLUSION: High Lp(a) levels and high ApoB/ApoA-Ι ratios before PCI are potential risk factors for CI-AKI.

Distinct Patterns of Host Adherence by Neisseria gonorrhoeae Isolated from Experimental Gonorrhea.

Neisseria gonorrhoeae (N. gonorrhoeae, gonococci, or GC), the etiologic agent of gonorrhea, is a human-obligate bacterial pathogen. The GC surface contains pili that mediate the adherence to host cells. Studies have shown that GC pili, coded by pilin genes, undergo remarkable changes during human experimental gonorrhea, possibly generated by DNA phase variation during infection. The question that arises is whether the changes in pilins can alter the adherence capacity of N. gonorrhoeae to host cells. In this study, six variants initially isolated from male volunteers infected with one single clone of GC were examined for their adherence patterns with human Chang conjunctiva cells. In this study, we showed that the variants showed distinct adherence patterns to this cell line under light microscopy and scanning electron microscopy. Moreover, two reisolates showed higher adherence capacities than that of the input strain. The results provide an additional example as to how the pilus variation may play a role in the pathogenesis of N. gonorrhoeae.

Genome-wide analysis of microsatellite and sex-linked marker identification in Gleditsia sinensis.

BACKGROUND: Gleditsia sinensis Lam. (Leguminosae), a dioecious perennial arbor, demonstrates important medicinal properties and economic value. These properties can be harnessed depending on the sex of the plant. However, the sex of the plants is difficult to identify accurately through morphological methods before the flowering. RESULTS: We used bulked segregant analysis to screen sex-specific simple sequence repeat (SSR) markers in G. sinensis. Five male and five female plants were pooled to form the male and female bulks, respectively, and subjected to whole-genome sequencing. After high-throughput sequencing, 5,350,359 sequences were obtained, in which 2,065,210 SSRs were searched. Among them, the number of duplicated SSRs was the highest. The male plants could reach 857,874, which accounted for 60.86% of the total number of male plants. The female plants could reach 1,447,603, which accounted for 56.25% of the total model of the female plants. Among all the nucleotide repeat types, the A/T-rich motif was the most abundant. A total of 309,516 female strain-specific SSRs were selected by clustering. After designing the primers, the male and female gene pools were amplified, and five pairs of primers (i.e., 27, 34, 36, 39, and 41) were found to amplify the differential bands in the male and female gene pools. Using the five pairs of primers, we performed PCR verification on 10 individuals of known sex, which constructed the gene pool. The female plants amplified a single fragment of lengths (i.e., 186, 305, 266, 203, and 260 bp) and no male plant strip, thereby completing the identification of the male and female sexes of the G. sinensis. CONCLUSIONS: This study provides accurate sex identification strategies between female and male plants, thus improving the utilization rate of G. sinensis resources.

Comparative transcriptomics analysis revealing flower trichome development during flower development in two Lonicera japonica Thunb. cultivars using RNA-seq.

BACKGROUND: Lonicera japonica Thunb. (L. japonica) has the functions of clearing away heat and detoxifying, broad-spectrum antibacterial and anti-virus, etc. More than 70% of anti-inflammatory and cold Chinese patent medicines contain L. japonica. Trichomes comprise specialized multicellular structures that have the capacity to synthesize and secrete secondary metabolites and protect plants from biotic and abiotic stresses. The extraction of trichome secretions has great commercial value. However, little is known about the trichome formation mechanism in L. japonica. Therefore, the study of trichome development between different varieties provides a basis for selecting suitable planting resources. RESULTS: Here, we present a genome-wide comparative transcriptome analysis between two L. japonica cultivars, toward the identification of biological processes and functional gene activities that occur during flowering stage trichome development. In this study, the density and average lengths of flower trichomes were at their highest during three-green periods (S2). Using the Illumina RNA-Seq method, we obtained 134,304 unigenes, 33,733 of which were differentially expressed. In an analysis of 40 differentially expressed unigenes (DEGs) involved in trichome development, 29 of these were transcription factors. The DEGs analysis of plant hormone signal transduction indicated that plant growth and development may be independent of gibberellin (GA) and cytokinine (CTK) signaling pathways, and plant stress may be independent of jasmonic acid (JA) and ethylene (ET) signaling pathways. We screened several genes involved in the floral biosynthesis of odors, tastes, colors, and plant hormones, and proposed biosynthetic pathways for sesquiterpenoid, triterpenoid, monoterpenoid, flavonoid, and plant hormones. Furthermore, 82 DEGs were assigned to cell cycles and 2616 were predicted as plant resistance genes (PRGs). CONCLUSIONS: This study provides a comprehensive characterization of the expression profiles of flower development during the seven developmental stages of L. japonica, thereby offering valuable insights into the molecular networks that underly flower development in L. japonica.

Yersinia pseudotuberculosis Exploits CD209 Receptors for Promoting Host Dissemination and Infection.

Yersinia pseudotuberculosis is a Gram-negative enteropathogen and causes gastrointestinal infections. It disseminates from gut to mesenteric lymph nodes (MLNs), spleen, and liver of infected humans and animals. Although the molecular mechanisms for dissemination and infection are unclear, many Gram-negative enteropathogens presumably invade the small intestine via Peyer's patches to initiate dissemination. In this study, we demonstrate that Y. pseudotuberculosis utilizes its lipopolysaccharide (LPS) core to interact with CD209 receptors, leading to invasion of human dendritic cells (DCs) and murine macrophages. These Y. pseudotuberculosis-CD209 interactions result in bacterial dissemination to MLNs, spleens, and livers of both wild-type and Peyer's patch-deficient mice. The blocking of the Y. pseudotuberculosis-CD209 interactions by expression of O-antigen and with oligosaccharides reduces infectivity. Based on the well-documented studies in which HIV-CD209 interaction leads to viral dissemination, we therefore propose an infection route for Y. pseudotuberculosis where this pathogen, after penetrating the intestinal mucosal membrane, hijacks the Y. pseudotuberculosis-CD209 interaction antigen-presenting cells to reach their target destinations, MLNs, spleens, and livers.

Salmonella enterica Serovar Typhimurium Interacts with CD209 Receptors To Promote Host Dissemination and Infection.

Salmonella enterica serovar Typhimurium, a Gram-negative bacterium, can cause infectious diseases ranging from gastroenteritis to systemic dissemination and infection. However, the molecular mechanisms underlying this bacterial dissemination have yet to be elucidated. A study indicated that using the lipopolysaccharide (LPS) core as a ligand, S Typhimurium was able to bind human dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (hCD209a), an HIV receptor that promotes viral dissemination by hijacking antigen-presenting cells (APCs). In this study, we showed that S Typhimurium interacted with CD209s, leading to the invasion of APCs and potentially the dissemination to regional lymph nodes, spleen, and liver in mice. Shielding of the exposed LPS core through the expression of O-antigen reduces dissemination and infection. Thus, we propose that similar to HIV, S Typhimurium may also utilize APCs via interactions with CD209s as a way to disseminate to the lymph nodes, spleen, and liver to initiate host infection.

Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial.

BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma. METHODS: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. FUNDING: F Hoffman-La Roche Ltd.

Glycemic Improvement with a Fixed-dose combination of DPP-4 inhibitor + metformin in patients with Type 2 diabetes (GIFT study).

This study investigates changes in A1C following a switch from dual therapy of metformin and DPP-4 inhibitor to a fixed-dose combination (FDC) of metformin + DPP-4 inhibitor following the introduction of the FDC in the provincial formulary. The LMC Diabetes Registry was queried retrospectively for patients with type 2 diabetes, aged between 18 and 80 years with at least one A1C recorded prior and ≥3 months post-switch. Five hundred and sixty-eight subjects with mean age 64 ± 12 years and mean A1C 7.7% ± 1.2% met study criteria. Overall, A1C was 0.3% lower post-switch to FDC (P < .01). In stratified analysis, subjects with baseline A1C between 7% and 10% had 0.4% lower A1C (P < .01), with 31% of these subjects reaching target A1C ≤7%, post-switch. A1C reduction was greater among patients with a higher baseline pill burden: 0.4% among those using ≥10 pills/day vs. 0.1% for those with <10 pills/day (P = .02). In this real-world study, switching to FDC of metformin + DPP-4 inhibitor was associated with a significant improvement in A1C. Switching to FDC, especially in patients with high pill burden, can improve A1C goal achievement in clinical practice.

[Study on breeding and pollination characteristics of Gleditsia sinensis].

To study the breeding system and pollination characteristics of Gleditsia sinensis, we observed the development of flower development and the processing of pollination, and determined the pollen viability and stigma acceptability by TTC and benzidine-hydrogen peroxide method and detected its breeding system using OCI value, P/O ratio and artificial pollination.The results showed that: ①G. sinensis are racemes, divided into bisexual inflorescences (only a small amount of inactive pollen) and male inflorescences (occasionally a few bisexual flowers), flowers hermaphrodite. ②Male flowers had the strongest pollen activity 4 h after flowering; the stigma receptivity of bisexual was the highest at 1 h after flowering, and pollination was the best in this time. ③The pollen tube had a few elongation when the bisexual flower is half-opened. The number of pollen tube and length significantly increased when blooming. The flower reaches the ovary and even enters the ovule to complete the fertilization. ④When the OCI=4 and P/O=11 684, it means that the breeding system was facultative, outcrossing, and requiring pollinators based on the results of the bagging experiment.There was parthenogenesis. ⑤The characteristics of saponin pollination were wind pollination and insect vector pollination, and pollinators were initially identified as Apis mellifera ligustica. All these results provides a theoretical and technical foundation for the new germplasm of G. sinensis.

FPR1, as a Potential Biomarker of Diagnosis and Infliximab Therapy Responses for Crohn's Disease, is Related to Disease Activity, Inflammation and Macrophage Polarization.

Purpose: Crohn's disease (CD) represents a multifaceted inflammatory gastrointestinal condition, with a profound significance placed on unraveling its molecular pathways to enhance both diagnostic capabilities and therapeutic interventions. This study focused on identifying a robust macrophage-related signatures (MacroSig) for diagnosing CD, emphasizing the role of FPR1 in macrophage polarization and its implications in CD. Patients and Methods: Expression profiles from intestinal biopsies and macrophages of 1804 CD patients were retrieved from the Gene Expression Omnibus (GEO). Utilizing CIBERSORTx, differential expression analysis, and weighted correlation network analysis to to identify macrophage-related genes (MRGs). By unsupervised clustering, distinct clusters of CD were identified. Potential biomarkers were identified via using four machine learning algorithms, leading to the establishment of MacroSig which combines insights from 12 machine learning algorithms. Furthermore, the expression of FPR1 was verified in intestinal biopsies of CD patients and two murine experimental colitis models. Finally, we further explored the role of FPR1 in macrophage polarization through single-cell analysis as well as through the study of RAW264.7 cells and peritoneal macrophages. Results: Two distinct clusters with differential levels of macrophage infiltration and inflammation were identified. The MacroSig, which included FPR1 and LILRB2, exhibited high diagnostic accuracy and outperformed existing biomarkers and signatures. Clinical analysis demonstrated a strong correlation of FPR1 with disease activity, endoscopic inflammation status, and response to infliximab treatment. The expression levels of FPR1 were validated in our CD cohort by immunohistochemistry and confirmed in two colitis mouse models. Single-cell analysis indicated that FPR1 is predominantly expressed in macrophages and monocytes. In vitro studies demonstrated that FPR1 was upregulated in M1 macrophages, and its activation promoted M1 polarization. Conclusion: We developed a promising diagnostic signature for CD, and targeting FPR1 to modulate macrophage polarization may represent a novel therapeutic strategy.

Association between Gut Microbiota and Biological Aging: A Two-Sample Mendelian Randomization Study.

Recent observational studies revealed an association between gut microbiota and aging, but whether gut microbiota are causally associated with the aging process remains unknown. We used a two-sample Mendelian randomization approach to investigate the causal association between gut microbiota and biological age acceleration using the largest available gut microbiota GWAS summary data from the MiBioGen consortium and GWAS data on biological age acceleration. We further conducted sensitivity analysis using MR-PRESSO, MR-Egger regression, Cochran Q test, and reverse MR analysis. Streptococcus (IVW, ß = 0.16, p = 0.0001) was causally associated with Bioage acceleration. Eubacterium (rectale group) (IVW, ß = 0.20, p = 0.0190), Sellimonas (IVW, ß = 0.06, p = 0.019), and Lachnospira (IVW, ß = -0.18, p = 0.01) were suggestive of causal associations with Bioage acceleration, with the latter being protective. Actinomyces (IVW, ß = 0.26, p = 0.0083), Butyricimonas (IVW, ß = 0.21, p = 0.0184), and Lachnospiraceae (FCS020 group) (IVW, ß = 0.24, p = 0.0194) were suggestive of causal associations with Phenoage acceleration. This Mendelian randomization study found that Streptococcus was causally associated with Bioage acceleration. Further randomized controlled trials are needed to investigate its role in the aging process.

CSF2 Impairs Nrf2 Signaling through the Akt/Mtor Pathway in the Development of Bladder Cancer.

Bladder Cancer (BCa) is one of the most common cancers of the urinary system. Colony-stimulating factor 2 (CSF2) is involved in many cancers, but not BCa. We investigated the effect of CSF2 on BCa in this study and the underlying molecular mechanisms. CSF2 mRNA levels in BCa were analyzed using the Cancer Genome Atlas (TCGA) database. Western blot was conducted to verify CSF2 expression in BCa tissue samples and cell lines. The effect of CSF2 on the growth of BCa cells was assessed by CCK8 and colony formation. To determine the migration and invasion capabilities of BCa cells, transwell analysis and wound healing assays were conducted. Next, western blot was used to explore the underlying mechanism. In the end, a xenografted BCa mouse model was established to examine the effects of CSF2 on tumorigenesis in vivo. Results showed that CSF2 mRNA was upregulated in BCa samples. Knocking down CSF2 significantly inhibited the proliferation and tumorigenesis of BCa cells in vitro and in vivo. Mechanism analysis revealed that CSF2 knockdown inhibited the proliferation and invasion of BCa cells via AKT/mTOR signaling. Based on these results, CSF2 promotes the proliferation and tumorigenesis of BCa.

A tutorial on sensitivity analyses in clinical trials: the what, why, when and how.

BACKGROUND: Sensitivity analyses play a crucial role in assessing the robustness of the findings or conclusions based on primary analyses of data in clinical trials. They are a critical way to assess the impact, effect or influence of key assumptions or variations--such as different methods of analysis, definitions of outcomes, protocol deviations, missing data, and outliers--on the overall conclusions of a study.The current paper is the second in a series of tutorial-type manuscripts intended to discuss and clarify aspects related to key methodological issues in the design and analysis of clinical trials. DISCUSSION: In this paper we will provide a detailed exploration of the key aspects of sensitivity analyses including: 1) what sensitivity analyses are, why they are needed, and how often they are used in practice; 2) the different types of sensitivity analyses that one can do, with examples from the literature; 3) some frequently asked questions about sensitivity analyses; and 4) some suggestions on how to report the results of sensitivity analyses in clinical trials. SUMMARY: When reporting on a clinical trial, we recommend including planned or posthoc sensitivity analyses, the corresponding rationale and results along with the discussion of the consequences of these analyses on the overall findings of the study.

The impact of a cardiovascular health awareness program (CHAP) on reducing blood pressure: a prospective cohort study.

BACKGROUND: Hypertension is an important and modifiable cardiovascular risk factor that remains under-detected and under-treated, especially in the older individuals. Community-led interventions that integrate primary health care and local resources are promising approaches to improve awareness and management of hypertension and other cardiovascular risk factors. We aimed to evaluate the effect of a community-based Cardiovascular Health Awareness Program (CHAP) on participants' blood pressure. METHODS: This study followed a cohort of community residents that participated in CHAP across 22 mid-sized Ontario communities over an 18-month period. The participants' baseline risk factors, including blood pressure, and subsequent measures of blood pressure were recorded. We employed a bivariate linear mixed-effect model to estimate the change of systolic and diastolic blood pressure over time among the participants who attended more than two CHAP sessions. RESULTS: Of 13,596 participants, 2498 attended more than two CHAP sessions. For those repeated participants (attending more than two sessions) initially identified with high blood pressure, the average reduction of systolic blood pressure was from 142 to 123 mmHg over an 18-month period, a monthly rate ratio of 0.992 (95% CI: 0.991,0.994; p < 0.01). Similarly, the average reduction of diastolic blood pressure was from 78 to 69 mmHg, a monthly rate ratio of 0.993 (95% CI: 0.991,0.994; p < 0.01). The average blood pressure of the participants with normal baseline blood pressure remained controlled and unchanged. We also found that older adult participants who lived alone, were diagnosed with hypertension, reported healthier eating habits, and presented with a higher baseline systolic blood pressure had significantly greater odds of attending more than one session. CONCLUSIONS: CHAP was associated with a reduction in systolic and diastolic blood pressure for those participants who attended more than one session. The magnitude of blood pressure reductions was significant clinically and statistically.

A look at the potential association between PICOT framing of a research question and the quality of reporting of analgesia RCTs.

BACKGROUND: Methodologists have proposed the formation of a good research question to initiate the process of developing a research protocol that will guide the design, conduct and analysis of randomized controlled trials (RCTs), and help improve the quality of reporting such studies. Five constituents of a good research question based on the PICOT framing include: Population, Intervention, Comparator, Outcome, and Time-frame of outcome assessment. The aim of this study was to analyze if the presence a structured research question, in PICOT format, in RCTs used within a 2010 meta-analysis investigating the effectiveness of femoral nerve blocks after total knee arthroplasty, is independently associated with improved quality of reporting. METHODS: Twenty-three RCT reports were assessed for the quality of reporting and then examined for the presence of the five constituents of a structured research question based on PICOT framing. We created a PICOT score (predictor variable), with a possible score between 0 and 5; one point for every constituent that was included. Our outcome variable was a 14 point overall reporting quality score (OQRS) and a 3 point key methodological items score (KMIS) based on the proper reporting of allocation concealment, blinding and numbers analysed using the intention-to-treat principle. Both scores, OQRS and KMIS, are based on the Consolidated Standards for Reporting Trials (CONSORT) statement. A multivariable regression analysis was conducted to determine if PICOT score was independently associated with OQRS and KMIS. RESULTS: A completely structured PICOT score question was found in 2 of the 23 RCTs evaluated. Although not statistically significant, higher PICOT was associated with higher OQRS [IRR: 1.267; 95% confidence interval (CI): 0.984, 1.630; p = 0.066] but not KMIS (1.061 (0.515, 2.188); 0.872). These results are comparable to those from a similar study in terms of the direction and range of IRRs estimates. The results need to be interpreted cautiously due to the small sample size. CONCLUSIONS: This study showed that PICOT framing of a research question in anesthesia-related RCTs is not often followed. Even though a statistically significant association with higher OQRS was not found, PICOT framing of a research question is still an important attribute within all RCTs.

The effect of regular physical activity on bone mineral density in post-menopausal women aged 75 and over: a retrospective analysis from the Canadian multicentre osteoporosis study.

BACKGROUND: Physical activity is known to benefit many physiological processes, including bone turnover. There are; however, currently no clinical guidelines regarding the most appropriate type, intensity and duration of activity to prevent bone loss. METHODS: To help address this gap in the literature, we performed a retrospective analysis of data from the Canadian Multicentre Osteoporosis Study (CaMos), a prospective cohort of 9423 adult patients, to determine the relationship between the amount of regular daily physical activity performed and bone mineral density. A total of 1169 female participants aged 75 and over provided information regarding their daily activity levels, including the amount of time spent each week performing physical activity at varying levels of intensity. Multiple and linear regression analyses were used to determine the effect of increasing amounts of this regular physical activity on bone mineral density. RESULTS: The results indicate that a step increase in the amount of physical activity performed each day resulted in a positive effect on bone mineral density at the hip, Ward's triangle, trochanter and femoral neck (B = 0.006 to 0.008, p < 0.05). Possible confounding factors such as the use of anti-resorptive therapy, body mass index and age were included in the analysis and suggested that age had a negative effect on bone density while body mass index had a positive effect. Anti-resorptive therapy provided a protective effect against loss of bone density. CONCLUSIONS: The data indicate that a step increase in the amount of daily activity, using simple, daily performed tasks, can help prevent decreases in post-menopausal bone mineral density.

Overcoming the compensatory increase in NRF2 induced by NPL4 inhibition enhances disulfiram/copper-induced oxidative stress and ferroptosis in renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney cancer, and it appears to be highly susceptible to ferroptosis. Disulfiram, an alcoholism drug, has been shown to have anticancer properties in various studies, including those on RCC. However, the mechanism of the anticancer effect of disulfiram/copper on RCC remains unclear. In this study, we investigated the impact of disulfiram/copper on RCC treatment using both RCC cells and mouse subcutaneous tumor models. Our findings demonstrate that disulfiram/copper treatment reduced the viability of RCC cells, inhibited their invasion and migration, and disrupted mitochondrial homeostasis, ultimately leading to oxidative stress and ferroptosis. Mechanistically, disulfiram/copper treatment prolonged the half-life of NRF2 and reduced its degradation, but had no effect on transcription, indicating that the disulfiram/copper-induced increase in NRF2 was not related to transcription. Furthermore, we observed that disulfiram/copper treatment reduced the expression of NPL4, a ubiquitin protein-proteasome system involved in NRF2 degradation, while overexpression of NPL4 reversed NRF2 levels and enhanced disulfiram/copper-induced oxidative stress and ferroptosis. These results suggest that overcoming the compensatory increase in NRF2 induced by NPL4 inhibition enhances disulfiram/copper-induced oxidative stress and ferroptosis in RCC. In addition, our in vivo experiments revealed that disulfiram/copper synergized with sorafenib to inhibit the growth of RCC cells and induce ferroptosis. In conclusion, our study sheds light on a possible mechanism for disulfiram/copper treatment in RCC and provides a potential synergistic strategy to overcome sorafenib resistance.

ß-Glucan Induces Training Immunity to Promote Antiviral Activity by Activating TBK1.

Many studies have shown that ß-glucan induces a trained immune phenotype in innate immune cells to defend against bacterial and fungal infections. The specific mechanism involves cellular metabolism and epigenetic reprogramming. However, it is unclear whether ß-glucan plays a role in antiviral infection. Therefore, this study investigated the role of trained immunity induced by Candida albicans and ß-glucan in antiviral innate immunity. It showed that C. albicans and ß-glucan promoted the expression of interferon-ß (IFN-ß) and interleukin-6 (IL-6) in mouse macrophages triggered by viral infection. In addition, ß-glucan pretreatment attenuated the pathological damage induced by the virus in mouse lungs and promoted the expression of IFN-ß. Mechanistically, ß-glucan could promote the phosphorylation and ubiquitination of TANK Binding Kinase 1 (TBK1), a key protein of the innate immune pathway. These results suggest that ß-glucan can promote innate antiviral immunity, and this bioactive material may be a potential therapeutic target for antiviral treatment.