Assessing the Risk of Bias in Randomized Clinical Trials With Large Language Models.

Importance: Large language models (LLMs) may facilitate the labor-intensive process of systematic reviews. However, the exact methods and reliability remain uncertain. Objective: To explore the feasibility and reliability of using LLMs to assess risk of bias (ROB) in randomized clinical trials (RCTs). Design, Setting, and Participants: A survey study was conducted between August 10, 2023, and October 30, 2023. Thirty RCTs were selected from published systematic reviews. Main Outcomes and Measures: A structured prompt was developed to guide ChatGPT (LLM 1) and Claude (LLM 2) in assessing the ROB in these RCTs using a modified version of the Cochrane ROB tool developed by the CLARITY group at McMaster University. Each RCT was assessed twice by both models, and the results were documented. The results were compared with an assessment by 3 experts, which was considered a criterion standard. Correct assessment rates, sensitivity, specificity, and F1 scores were calculated to reflect accuracy, both overall and for each domain of the Cochrane ROB tool; consistent assessment rates and Cohen κ were calculated to gauge consistency; and assessment time was calculated to measure efficiency. Performance between the 2 models was compared using risk differences. Results: Both models demonstrated high correct assessment rates. LLM 1 reached a mean correct assessment rate of 84.5% (95% CI, 81.5%-87.3%), and LLM 2 reached a significantly higher rate of 89.5% (95% CI, 87.0%-91.8%). The risk difference between the 2 models was 0.05 (95% CI, 0.01-0.09). In most domains, domain-specific correct rates were around 80% to 90%; however, sensitivity below 0.80 was observed in domains 1 (random sequence generation), 2 (allocation concealment), and 6 (other concerns). Domains 4 (missing outcome data), 5 (selective outcome reporting), and 6 had F1 scores below 0.50. The consistent rates between the 2 assessments were 84.0% for LLM 1 and 87.3% for LLM 2. LLM 1's κ exceeded 0.80 in 7 and LLM 2's in 8 domains. The mean (SD) time needed for assessment was 77 (16) seconds for LLM 1 and 53 (12) seconds for LLM 2. Conclusions: In this survey study of applying LLMs for ROB assessment, LLM 1 and LLM 2 demonstrated substantial accuracy and consistency in evaluating RCTs, suggesting their potential as supportive tools in systematic review processes.

Commonly Drawn Immunologic and Inflammatory Markers as Risk Predictors for Anal Cancer in Veterans Living With HIV.

OBJECTIVES: This study aimed to determine if immune inflammatory markers (neutrophil lymphocyte ratio [NLR], platelet lymphocyte ratio [PLR], and prognostic nutritional index [PNI]) correlate with anal cancer risk in people living with HIV and to compare these markers with the CD4/CD8 ratio. MATERIALS AND METHODS: This is a regional retrospective cohort study of veterans living with HIV who were screened for or diagnosed with anal neoplasia or cancer from 2001 to 2019. The NLR, PLR, PNI, and CD4/CD8 ratio within 1 year of anal pathology results were computed. Patients with anal cancer were compared to patients without anal cancer. Regression modeling was used to estimate the odds of developing anal cancer. RESULTS: Three hundred thirty-four patients were included (37 with anal cancer, 297 without anal cancer). In patients with anal cancer, NLR and PLR were higher (2.17 vs 1.69, p = .04; 140 vs 110, p = .02, respectively), while PNI and CD4/CD8 ratio were lower (44.65 vs 50.01, p < .001; 0.35 vs 0.80, p < .001, respectively). On multivariate logistic regression modeling, only PNI (odds ratio, 0.90; p = .001) and CD4/CD8 ratio (odds ratio, 0.05; p < .001) were associated with increased anal cancer risk. CONCLUSIONS: Although NLR and PLR independently correlate with anal cancer risk, when controlling for other risk predictors, only PNI and CD4/CD8 ratio were statistically significant biomarkers for anal cancer. The CD4/CD8 ratio is the strongest immune inflammatory marker that predicts risk of anal cancer among veterans living with HIV.

Multi-modular metabolic engineering of heme synthesis in Corynebacterium glutamicum.

Heme, an iron-containing porphyrin derivative, holds great promise in fields like medicine, food production and chemicals. Here, we developed an engineered Corynebacterium glutamicum strain for efficient heme production by combining modular engineering and RBS engineering. The whole heme biosynthetic pathway was methodically divided into 5-ALA synthetic module, uroporphyrinogen III (UPG III) synthetic module and heme synthetic module for further construction and optimization. Three heme synthetic modules were compared and the siroheme-dependent (SHD) pathway was identified to be optimal in C. glutamicum for the first time. To further improve heme production, the expression of genes in UPG III synthetic module and heme synthetic module was coordinated optimized through RBS engineering, respectively. Subsequently, heme oxygenase was knocked out to reduce heme degradation. The engineered strain HS12 showed a maximum iron-containing porphyrin derivatives titer of 1592 mg/L with the extracellular secretion rate of 45.5% in fed-batch fermentation. Our study constructed a C. glutamicum chassis strain for efficient heme accumulation, which was beneficial for the advancement of efficient heme and other porphyrins production.

Analysis of >15 000 Solid Organ Transplant Recipients Reveals Nonanal Genitourinary HPV-related Disease as Highest Risk Predictor for Anal Squamous Intraepithelial Lesions/Anal Cancer.

BACKGROUND: Solid organ transplantation is a risk predictor for virally-mediated anal squamous intraepithelial lesions and cancer (anal disease). Precancerous squamous intraepithelial lesions can be detected by screening, and treatment may prevent cancer progression. Screening recommendations are not well defined. We aim to define prevalence and describe risk predictors for anal disease in a large population of solid organ transplant recipients. METHODS: Retrospective single-center cohort analysis included solid organ transplant recipients cared for between 2001 and 2022 (N = 15 362). The cohort of recipients who developed anal disease was compared with those who did not. Greedy propensity score matching was performed for organ-specific recipients, and time-to-event analysis for the development of anal disease was performed in those with genitourinary human papilloma virus (HPV) disease versus those without. RESULTS: Prevalence of anal disease was 0.6% (cancer 0.2%). The average years from transplant to the diagnosis of anal disease was 11.67. Anal disease was more common in women (68.5% versus 31.5%, P < 0.001), patients who had other HPV-related genitourinary diseases (40.4% versus 0.6%, P < 0.001), who were of younger age at transplant (39.62 versus 46.58, P < 0.001), and had increased years from transplant (17.06 versus 12.57, P < 0.001). In multivariate analysis, the odds of anal disease increased by 4% each year posttransplant. History of genitourinary HPV disease (odds ratio 69.63) and female sex (odds ratio 1.96) were the most significant risk predictors for anal disease. CONCLUSIONS: The prevalence of anal cancer among solid organ transplant recipients was equal to the general population (0.2%). Due to the low prevalence of overall disease, these data suggest that anal screenings in transplant recipients should be targeted to higher-risk subsets: female recipients farther out from transplant and patients with genitourinary HPV-related diseases.

Elucidating the mechanisms underlying astrocyte-microglia crosstalk in hippocampal neuroinflammation induced by acute diquat exposure.

The transition from paraquat (PQ) to diquat (DQ), both organic dication herbicides, in China has led to significant increases in the number of acute DQ poisoning cases. Case studies have shown that acute DQ poisoning resulted in injury to the central nervous system (CNS), but the mechanism underlying the injury remains to be explored. The present study aimed to investigate how DQ influenced purinergic signaling between astrocytes and microglia and whether extracellular ATP (eATP) was involved in promoting neuroinflammation induced by acute DQ toxicity through the activation of the P2X4/NLRP3 signaling pathway. We constructed a rat model of acute DQ toxicity to observe the pathological changes in hippocampal tissues after DQ exposure and measure the expression levels of IL-1ß and TNF-α in the hippocampal tissue. We also established an in vitro co-culture model of C6 astrocytes and BV-2 microglia using transwell chambers, measured the amount of eATP secreted into C6 astrocytes after DQ treatment, and assessed the inflammatory response and changes in the P2X4/NLRP3 signaling pathway in BV-2 microglia. The results showed that the neurons in the hippocampal tissue of rats exhibited loose arrangement, nuclear consolidation, and necrosis after DQ exposure, and IL-1ß and TNF-α levels were signification higher in the hippocampal tissue after DQ exposure. DQ exposure to the co-cultured cells induced an increase in ATP secretion from C6 astrocytes as well as a significant increase of P2X4, NLRP3, IL-1ß, and IL-18 expression in BV-2 microglia. In contrast, pretreatment of C6 astrocytes with apyrase (an ATP hydrolase) resulted in a significant decrease of P2X4, NLRP3, IL-1ß, and IL-18 expression in BV-2 microglia. Furthermore, inhibition of P2X4 expression in BV-2 microglia by transfection with si-P2X4 effectively reversed the increase of NLRP3, IL-1ß, and IL-18 in BV-2 microglia induced by DQ when co-cultured with C6 astrocytes. These results indicate that astrocytes can activate the P2X4/NLRP3 signaling pathway in microglia through the DQ-induced extracellular release of ATP to promote neuroinflammation in rat hippocampal tissue.

A generalized QUCESOP method with evaluating CEST peak overlap.

The overlapping peaks of the target chemical exchange saturation transfer (CEST) solutes and other unknown CEST solutes affect the quantification results and accuracy of the chemical exchange parameters-the fractional concentration, f b , exchange rate, k b , and transverse relaxation rate, R 2 b -for the target solutes. However, to date, no method has been established for assessing the overlapping peaks. This study aimed to develop a method for quantifying the f b , k b , and R 2 b values of a specific CEST solute, as well as assessing the overlap between the CEST peaks of the specific solute(s) and other unknown solutes. A simplified R 1 ρ model was proposed, assuming linear approximation of the other solutes' contributions to R 1 ρ . A CEST data acquisition scheme was applied with various saturation offsets and saturation powers. In addition to fitting the f b , k b , and R 2 b values of the specific solute, the overlapping condition was evaluated based on the root mean square error (RMSE) between the trajectories of the acquired and synthesized data. Single-solute and multi-solute phantoms with various phosphocreatine (PCr) concentrations and pH values were used to calculate the f b and k b of PCr and the corresponding RMSE. The feasibility of RMSE for evaluating the overlapping condition, and the accurate fitting of f b and k b in weak overlapping conditions, were verified. Furthermore, the method was employed to quantify the nuclear Overhauser effect signal in rat brains and the PCr signal in rat skeletal muscles, providing results that were consistent with those reported in previous studies. In summary, the proposed approach can be applied to evaluate the overlapping condition of CEST peaks and quantify the f b , k b , and R 2 b values of specific solutes, if the weak overlapping condition is satisfied.

Small Monetary Incentives Lead to Greater Adherence in a Weight Loss Program.

PURPOSE: Understand how weekly monetary incentives for dietary tracking and/or weight loss impact 6-month weight loss behavioral adherence. DESIGN: Secondary analysis of participants randomized to one of four conditions in a behavioral weight loss intervention: incentives for dietary tracking, incentives for weight loss, both, or none. SETTING: Participants were asked to self-weigh at least twice weekly, log food and drink in a mobile application five days weekly, and attend bi-weekly, group-based classes. SAMPLE: Data from (n = 91) adults with obesity who completed a 24-week behavioral weight loss intervention of whom 88% were female and 74% Non-Hispanic White, were analyzed. MEASURES: Non-adherence to weight and dietary self-monitoring was defined as the second week of not meeting criteria. Class attendance was also tracked. ANALYSIS: Kaplan-Meier analyses were used to examine differences across the four conditions. RESULTS: Participants incentivized for dietary self-monitoring had an average 15.8 weeks (SE:1.2) until the first non-adherent week compared to 5.9 weeks (SE:0.8) for those not incentivized for dietary self-monitoring (P < .01). Those incentivized for weight loss had an average 18.0 weeks (SE:1.02) of self-weighing until the first non-adherent week compared to 13.5 weeks (SE:1.3) for those not incentivized for weight loss (P = .02). No difference in class attendance was observed. CONCLUSIONS: Incentivizing behaviors associated with weight loss improved adherence to those behaviors and does not appear to spill over to non-incentivized behaviors.

Bibliometric analysis of global literature productivity in systemic lupus erythematosus from 2013 to 2022.

BACKGROUND: Bibliometric analysis is a mature method for quantitative evaluation of academic productivity. In view of the rapid development of research in the field of systemic lupus erythematosus (SLE) in the past decade, we used bibliometric methods to comprehensively analyze the literature in the field of SLE from 2013 to 2022. METHODS: The relevant literature in the field of SLE from 2013 to 2022 was screened in the Web of Science Core Collection database. After obtaining and sorting out the data, CiteSpace and VOSviewer software were used to visualize the relevant data, and SPSS software was used for scientific statistics. RESULTS: A total of 18,450 publications were included in this study. The number of articles published over the past 10 years has generally shown an upward trend, while Altmetric attention scores have also shown a clear upward trend in general and in most countries. Citation analysis and Altmetric analysis can mutually prove and supplement the influence of papers. The USA, China, Japan, Italy, and the UK are the most productive countries, but China and Japan are significantly inferior to other countries in terms of research influence. Four of the top ten authors are at the center of the collaboration network. LUPUS is the most contributing journal. The theme of systemic lupus erythematosus research mainly focuses on the pathogenesis, treatment, and management of SLE, and the emerging trend is related research on machine learning and immune cells. CONCLUSION: This study shows the research status of SLE, clarifies the main contributors in this field, discusses and analyzes the research hotspots and trends in this field, and provides reference for further research in this field to promote the development of SLE research. Key Points • Through bibliometric analysis, Altmetric analysis, and visual analysis, we reveal the global productivity characteristics of SLE-related papers in the past 10 years. • The number of global SLE-related studies has shown a significant increase, indicating that SLE is still a hot topic and deserves further study. • Citation analysis and Altmetric analysis can mutually prove and supplement the influence of papers, and the attention of related literature among non-professional researchers is increasing. • The theme of SLE research mainly focuses on the pathogenesis, treatment, and management of SLE. The emerging trend is machine learning and immune cells, which may provide new strategies for the diagnosis and treatment of SLE in the future.

A systematic review of prediction models for spontaneous preterm birth in singleton asymptomatic pregnant women with risk factors.

Backgrounds: Spontaneous preterm birth (SPB) is a global problem. Early screening, identification, and prevention in asymptomatic pregnant women with risk factors for preterm birth can help reduce the incidence and mortality of preterm births. Therefore, this study systematically reviewed prediction models for spontaneous preterm birth, summarised the model characteristics, and appraised their quality to identify the best-performing prediction model for clinical decision-making. Methods: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc, VIP Database, and Wanfang Data were searched up to September 27, 2021. Prediction models for spontaneous preterm births in singleton asymptomatic pregnant women with risk factors were eligible for inclusion. Six independent reviewers selected the eligible studies and extracted data from the prediction models. The findings were summarised using descriptive statistics and visual plots. Results: Twelve studies with twelve developmental models were included. Discriminative performance was reported in 11 studies, with an Area Under the Curve (AUC) ranging from 0.75 to 0.95. The AUCs of the seven models were greater than 0.85. Cervical length (CL) is the most commonly used predictor of spontaneous preterm birth. A total of 91.7% of the studies had a high risk of bias in the analysis domain, mainly because of the small sample size and lack of adjustment for overfitting. Conclusion: The accuracy of the models for spontaneous preterm births in singleton asymptomatic women with risk factors was good. However, these models are not widely used in clinical practice because they lack replicability and transparency. Future studies should transparently report methodological details and consider more meaningful predictors with new progress in research on preterm birth.

Potential causal association between aspirin use and the reduced risk of hayfever or allergic rhinitis: a Mendelian randomization study.

Background: The evidence from observational studies on the association between the use of aspirin and the risk of hayfever or allergic rhinitis is conflicting, with a dearth of high-quality randomized controlled trials. Objective: This study aims to investigate the causal relationship between aspirin use and the risk of hayfever or allergic rhinitis. Methods: We conducted a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), weighted median, and MR-Egger regression methods. We utilized publicly available summary statistics datasets from genome-wide association studies (GWAS) meta-analyses on aspirin use in individuals of European descent (n = 337,159) as the exposure variable, and a GWAS on doctor-diagnosed hayfever or allergic rhinitis in individuals from the UK Biobank (n = 83,529) as the outcome variable. Results: We identified 7 single nucleotide polymorphisms (SNPs) at genome-wide significance from the GWASs associated with aspirin use as instrumental variables (P<5×10-8; linkage disequilibrium r2 <0.1). The IVW method provided evidence supporting a causal association between aspirin use and reduced risk of hayfever or allergic rhinitis (ß = -0.349, SE = 0.1356, P = 0.01008). MR-Egger regression indicated no causal association between aspirin use and hayfever or allergic rhinitis (ß = -0.3742, SE = 0.3809, P = 0.371), but the weighted median approach yielded evidence of a causal association (ß = -0.4155, SE = 0.1657, P = 0.01216). Cochran's Q test and the funnel plot indicated no evidence of heterogeneity and asymmetry, indicating no directional pleiotropy. Conclusion: The findings of the MR analysis support a potential causal relationship between aspirin use and the reduced risk of hayfever or allergic rhinitis.

Ultrasonic vocalization phenotypes in the Ts65Dn and Dp(16)1Yey mouse models of Down syndrome.

Down syndrome (DS) is a developmental disorder associated with a high incidence of challenges in vocal communication. DS can involve medical co-morbidities and structural social factors that may impact communication outcomes, which can present difficulties for the study of vocal communication challenges. Mouse models of DS may be used to study vocal communication differences associated with this syndrome and allow for greater control and consistency of environmental factors. Prior work has demonstrated differences in ultrasonic vocalization (USV) of the Ts65Dn mouse model of DS at a young adult age, however it is not known how USV characteristics are manifested at mature ages. Given that the aging process and age-related co-morbidities may also impact communication in DS, addressing this gap in knowledge may be of value for efforts to understand communication difficulties in DS across the lifespan. The current study hypothesized that the Ts65Dn and Dp(16)1Yey mouse models of DS would demonstrate differences in multiple measures of USV communication at a mature adult age of 5 months. METHODS: Ts65Dn mice (n = 16) and euploid controls (n = 19), as well as Dp(16)1Yey mice (n = 20) and wild-type controls (n = 22), were evaluated at 5 months of age for USV production using a mating paradigm. Video footage of USV sessions were analyzed to quantify social behaviors of male mice during USV testing sessions. USV recordings were analyzed using Deepsqueak software to identify 10 vocalization types, which were quantified for 11 acoustic measures. RESULTS: Ts65Dn, but not Dp(16)1Yey, showed significantly lower proportions of USVs classified as Step Up, Short, and Frequency Steps, and significantly higher proportions of USVs classified as Inverted U, than euploid controls. Both Ts65Dn and Dp(16)1Yey groups had significantly greater values for power and tonality for USVs than respective control groups. While Ts65Dn showed lower frequencies than controls, Dp(16)1Yey showed higher frequencies than controls. Finally, Ts65Dn showed reductions in a measure of complexity for some call types. No significant differences between genotype groups were identified in analysis of behaviors during testing sessions. CONCLUSION: While both Ts65Dn and Dp(16)1Yey show significant differences in USV measures at 5 months of age, of the two models, Ts65Dn shows a relatively greater numbers of differences. Characterization of communication phenotypes in mouse models of DS may be helpful in laying the foundation for future translational advances in the area of communication difficulties associated with DS.

Preparation of Self-Coating Al2O3 Bonded SiAlON Porous Ceramics Using Aluminum Dross and Silicon Solid Waste under Ambient Air Atmosphere.

Al2O3-bonded SiAlON ceramic with self-coating was prepared using aluminum dross and silicon solid waste as starting materials under ambient air conditions. The changes in phase, microstructure, and physical properties of the ceramic with temperature were analyzed and the formation mechanism of the SiAlON phase was elucidated. The results showed that higher temperature was more suitable for the preparation of SiAlON ceramics. As the temperature increased from 1400 to 1600 °C, the main phases in the ceramic transformed from mullite, Al2O3, and SiAlON to Al2O3 and SiAlON. An Al2O3-rich layer spontaneously coated the surface of the porous ceramic as Al melted and oxidized at high temperature. The thickness of this layer decreased as the temperature increased. The presence of Al2O3-rich coating layer impeded air flow, allowing nitriding of Si and Al, and the formation of the SiAlON phase in ambient air conditions. This study not only presents a strategy to successfully recycle aluminum dross and silicon solid waste but also offers a straightforward approach to preparing SiAlON material in air atmosphere.

Association of soft drinks and 100% fruit juice consumption with risk of cancer: a systematic review and dose-response meta-analysis of prospective cohort studies.

BACKGROUND: Studies of the associations between soft drinks and the risk of cancer showed inconsistent results. No previous published systematic reviews and meta-analysis has investigated a dose-response association between exposure dose and cancer risk or assessed the certainty of currently available evidence. Therefore, we aim to demonstrate the associations and assessed the certainty of the evidence to show our confidence in the associations. METHODS: We searched Embase, PubMed, Web of Science, and the Cochrane Library from inception to Jun 2022, to include relevant prospective cohort studies. We used a restricted cubic spline model to conduct a dose-response meta-analysis and calculated the absolute effect estimates to present the results. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence. RESULTS: Forty-two articles including on 37 cohorts enrolled 4,518,547 participants were included. With low certainty evidence, increased consumption of sugar-sweetened beverages (SSBs) per 250 mL/day was significantly associated with a 17% greater risk of breast cancer, a 10% greater risk of colorectal cancer, a 30% greater risk of biliary tract cancer, and a 10% greater risk of prostate cancer; increased consumption of artificially sweetened beverages (ASBs)re per 250 mL/day was significantly associated with a 16% greater risk of leukemia; increased consumption of 100% fruit juice per 250 mL/day was significantly associated with a 31% greater risk of overall cancer, 22% greater risk of melanoma, 2% greater risk of squamous cell carcinoma, and 29% greater risk of thyroid cancer. The associations with other specific cancer were no significant. We found linear dose-response associations between consumption of SSBs and the risk of breast and kidney cancer, and between consumption of ASBs and 100% fruit juices and the risk of pancreatic cancer. CONCLUSIONS: An increment in consumption of SSBs of 250 mL/day was positively associated with increased risk of breast, colorectal, and biliary tract cancer. Fruit juices consumption was also positively associated with the risk of overall cancer, thyroid cancer, and melanoma. The magnitude of absolute effects, however, was small and mainly based on low or very low certainty of evidence. The association of ASBs consumption with specific cancer risk was uncertain. TRIAL REGISTRATION: PROSPERO: CRD42020152223.

Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Ovid Medline, Embase, and Cochrane Central up to 14 October 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach. RESULTS: The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference -8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes (https://matchit.magicevidence.org/230125dist-diabetes). CONCLUSIONS: This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022325948.

Microbial Synthesis of Heme b: Biosynthetic Pathways, Current Strategies, Detection, and Future Prospects.

Heme b, which is characterized by a ferrous ion and a porphyrin macrocycle, acts as a prosthetic group for many enzymes and contributes to various physiological processes. Consequently, it has wide applications in medicine, food, chemical production, and other burgeoning fields. Due to the shortcomings of chemical syntheses and bio-extraction techniques, alternative biotechnological methods have drawn increasing attention. In this review, we provide the first systematic summary of the progress in the microbial synthesis of heme b. Three different pathways are described in detail, and the metabolic engineering strategies for the biosynthesis of heme b via the protoporphyrin-dependent and coproporphyrin-dependent pathways are highlighted. The UV spectrophotometric detection of heme b is gradually being replaced by newly developed detection methods, such as HPLC and biosensors, and for the first time, this review summarizes the methods used in recent years. Finally, we discuss the future prospects, with an emphasis on the potential strategies for improving the biosynthesis of heme b and understanding the regulatory mechanisms for building efficient microbial cell factories.

Duration of Time CD4/CD8 Ratio is Below 0.5 is Associated with Progression to Anal Cancer in Patients with HIV and High-Grade Dysplasia.

BACKGROUND: A CD4/CD8 ratio < 0.5 is associated with increased risk of advanced anal disease (AAD) but it is unknown if duration below 0.5 matters. The purpose of this study was to determine if duration of a CD4/CD8 ratio < 0.5 is associated with increased risk of invasive anal cancer (IC) in people living with HIV and high-grade dysplasia (HSIL). METHODS: This single institution, retrospective study used the University of Wisconsin Hospital and Clinics Anal Dysplasia and Anal Cancer Database. Patients with IC versus HSIL alone were compared. Independent variables were mean and percentage of time the CD4/CD8 ratio was < 0.5. Multivariate logistic regression was performed to estimate the adjusted odds of anal cancer. RESULTS: We identified 107 patients with HIV infection and AAD (87 with HSIL, 20 with IC). A history of smoking was significantly associated with the development of IC (95% in patients with IC vs. 64% in patients with HSIL; p = 0.015). Mean time the CD4/CD8 ratio was < 0.5 was significantly longer in patients with IC compared with patients with HSIL (7.7 years vs. 3.8 years; p = 0.002). Similarly, the mean percentage of time the CD4/CD8 ratio was < 0.5 was higher in those with IC versus those with HSIL (80% vs. 55%; p = 0.009). On multivariate analysis, duration CD4/CD8 ratio was < 0.5 was associated with increased odds of developing IC (odds ratio 1.25, 95% confidence interval 1.02-1.53; p = 0.034). CONCLUSIONS: In this retrospective, single-institution study of a cohort of people living with HIV and HSIL, increasing duration the CD4/CD8 ratio was < 0.5 was associated with increased odds of developing IC. Monitoring the number of years the CD4/CD8 ratio is < 0.5 could inform decision making in patients with HIV infection and HSIL.

Bismuth-based metal-organic framework peroxidase-mimic nanozyme: Preparation and mechanism for colorimetric-converted ultra-trace electrochemical sensing of chromium ion.

A colorimetric-electrochemical dual-mode analytical method based on bismuth metal-organic framework nanozyme was developed for label-free and trace/ultra-trace Cr6+ detection. 3D ball-flower shaped bismuth oxide formate (BiOCOOH) was used as the precursor and template to facilely construct the metal-organic framework nanozyme BiO-BDC-NH2, which possesses intrinsic peroxidase-mimic activity to effectively catalyze the colorless 3,3',5,5'-tetramethylbenzidine into blue oxidation products in the presence of hydrogen peroxide. Based on Cr6+ to promote the peroxide-mimic activity of BiO-BDC-NH2 nanozyme, a colorimetric method for Cr6+ detection was developed with the detection limit of 0.44 ng mL-1. Cr6+ can be electrochemically reduced to Cr3+ that would specifically inhibit the peroxidase-mimic activity of BiO-BDC-NH2 nanozyme. Thus, the colorimetric system for Cr6+ detection was converted into a low-toxic and signal-off electrochemical sensor. The electrochemical model showed upgraded sensitivity and a lower detection limit of 9.00 pg mL-1. The dual-model method was developed for selective appropriate sensing instruments in different detection scenarios, which can provide built-in correction for environmental effects, as well as the development and utilization of dual-signal sensing platforms for trace to ultra-trace Cr6+ rapid assay.

Long-Term Follow-up of 64 Patients With Idiopathic Subglottic Stenosis: Treatment Pathways, Outcomes, and Impact of Serial Intralesional Steroid Injections.

OBJECTIVE: To describe treatment pathways and long-term outcomes in 64 patients with idiopathic subglottic stenosis (iSGS), including the impact of serial intralesional steroid injection (SILSI) on degree of stenosis, need for subsequent operation, and patient-reported outcome measures. METHODS: Retrospective review of 64 female patients with iSGS undergoing varied management approaches, 57 of whom underwent SILSI as at least part of their care. Treatment pathways included SILSI only, endoscopic intervention followed by SILSI only, endoscopic interventions only, endoscopic intervention followed by SILSI followed by need for repeat endoscopic intervention, open surgery, and tracheotomy. Outcomes assessed included subjectively estimated percent airway stenosis, dyspnea index (DI), modified medical research council (MMRC) dyspnea scale, voice handicap index-10 (VHI-10), number of operative and office-based procedures performed, need for subsequent operative intervention, and inter-operative interval. RESULTS: Treatment pathways included SILSI alone (n = 6), endoscopic intervention(s) followed by SILSI only (n = 31), SILSI followed by additional endoscopic or office-based procedures (n = 16), open surgery (n = 3), and tracheostomy (n = 4). 57 of 64 patients underwent SILSI as at least part of their treatment. Inter-operative interval was increased after starting SILSI. Of patients undergoing SILSI, those with more procedures or shorter inter-operative interval prior to SILSI were more likely to return to the operating room. Estimated stenosis, DI, MMRC, and VHI-10 decreased with SILSI. Stenosis was not correlated with DI, MMRC, or VHI-10, though DI was correlated with both MMRC and VHI-10 score. CONCLUSION: Of 57 patients undergoing SILSI, 37 did not require further operative intervention. Improvements in inter-operative interval, dyspnea, and voice were observed across patients. Randomized trials to identify which patients may benefit most from SILSI are warranted.