Guidance of development, validation, and evaluation of algorithms for populating health status in observational studies of routinely collected data (DEVELOP-RCD).

BACKGROUND: In recent years, there has been a growing trend in the utilization of observational studies that make use of routinely collected healthcare data (RCD). These studies rely on algorithms to identify specific health conditions (e.g. diabetes or sepsis) for statistical analyses. However, there has been substantial variation in the algorithm development and validation, leading to frequently suboptimal performance and posing a significant threat to the validity of study findings. Unfortunately, these issues are often overlooked. METHODS: We systematically developed guidance for the development, validation, and evaluation of algorithms designed to identify health status (DEVELOP-RCD). Our initial efforts involved conducting both a narrative review and a systematic review of published studies on the concepts and methodological issues related to algorithm development, validation, and evaluation. Subsequently, we conducted an empirical study on an algorithm for identifying sepsis. Based on these findings, we formulated specific workflow and recommendations for algorithm development, validation, and evaluation within the guidance. Finally, the guidance underwent independent review by a panel of 20 external experts who then convened a consensus meeting to finalize it. RESULTS: A standardized workflow for algorithm development, validation, and evaluation was established. Guided by specific health status considerations, the workflow comprises four integrated steps: assessing an existing algorithm's suitability for the target health status; developing a new algorithm using recommended methods; validating the algorithm using prescribed performance measures; and evaluating the impact of the algorithm on study results. Additionally, 13 good practice recommendations were formulated with detailed explanations. Furthermore, a practical study on sepsis identification was included to demonstrate the application of this guidance. CONCLUSIONS: The establishment of guidance is intended to aid researchers and clinicians in the appropriate and accurate development and application of algorithms for identifying health status from RCD. This guidance has the potential to enhance the credibility of findings from observational studies involving RCD.

A Bayesian bias-adjusted random-effects model for synthesizing evidence from randomized controlled trials and nonrandomized studies of interventions.

OBJECTIVE: An important consideration when combining RCTs and NRSIs is how to address their potential biases in the pooled estimates. This study aimed to propose a Bayesian bias-adjusted random effects model for the synthesis of evidence from RCTs and NRSIs. METHODS: We present a Bayesian bias-adjusted random effects model based on power prior method, which combines the likelihood contribution of the NRSIs, raised to the power parameter of alpha, with the likelihood of the RCT data, modeled with an additive bias. The method was illustrated using a meta-analysis on the association between low-dose methotrexate exposure and melanoma. We also combined RCTs and NRSIs using the naïve data synthesis. RESULTS: The results including only RCTs has a posterior median and 95% credible interval (CrI) of 1.18 (0.31-4.04), the posterior probability of any harm (> 1.0) and a meaningful association (> 1.15) were 0.61 and 0.52, respectively. The posterior median and 95% CrI based on the naïve data synthesis resulted in 1.17 (0.96-1.47), and the posterior probability of any harm and a meaningful association were 0.96 and 0.60, respectively. For the Bayesian bias-adjusted analysis, the median OR was 1.16 (95% CrI: 0.83-1.71), and the posterior probabilities of any and a meaningful clinical association were 0.88 and 0.53, respectively. CONCLUSIONS: The results indicated that integrating NRSIs into meta-analysis could increase the certainty of the body of evidence. However, directly combining RCTs and NRSIs in the same meta-analysis without distinction may lead to misleading conclusions.

Cadherin-18 loss in prospermatogonia and spermatogonial stem cells enhances cell adhesion through a compensatory mechanism.

Extracellular membrane proteins are crucial for mediating cell attachment, recognition, and signal transduction in the testicular microenvironment, particularly germline stem cells. Cadherin 18 (CDH18), a type II classical cadherin, is primarily expressed in the nervous and reproductive systems. Here, we investigated the expression of CDH18 in neonatal porcine prospermatogonia (ProSGs) and murine spermatogonial stem cells (SSCs). Disruption of CDH18 expression did not adversely affect cell morphology, proliferation, self-renewal, or differentiation in cultured porcine ProSGs, but enhanced cell adhesion and prolonged cell maintenance. Transcriptomic analysis indicated that the down-regulation of CDH18 in ProSGs significantly up-regulated genes and signaling pathways associated with cell adhesion. To further elucidate the function of CDH18 in germ cells, Cdh18 knockout mice were generated, which exhibited normal testicular morphology, histology, and spermatogenesis. Transcriptomic analysis showed increased expression of genes associated with adhesion, consistent with the observations in porcine ProSGs. The interaction of CDH18 with ß-catenin and JAK2 in both porcine ProSGs and murine SSCs suggested an inhibitory effect on the canonical Wnt and JAK-STAT signaling pathways during CDH18 deficiency. Collectively, these findings highlight the crucial role of CDH18 in regulating cell adhesion in porcine ProSGs and mouse SSCs. Understanding this regulatory mechanism provides significant insights into the testicular niche.

The Effects of Pore Defects in π-Extended Pentadecabenzo[9]helicene.

The introduction of precise pore defects into nanocarbon structures results in the emergence of distinct physicochemical characteristics. However, there is a lack of research on non-planar chiral nanographene involving precise pore defects. Herein, we have developed two analogues to the π-extended pentadecabenzo[9]helicene (EP9H) containing embedded pore defects. Each molecule, namely extended dodecabenzo[7]helicene (ED7H; 1) or extended nonabenzo[5]helicene (EN5H; 2), exhibits dual-state emission. Significantly, the value of |glum| of 1 is exceptionally high at 1.41 × 10-2 in solution and BCPL as 254 M-1 cm-1. In PMMA film, |glum| of 1 is 8.56 × 10-3, and in powder film, it is 5.00 × 10-3. This study demonstrates that nanocarbon molecules with pore defects exhibit dual-state emission properties while maintaining quite good chiral luminescence properties. It was distinguished from the aggregation-caused quenching (ACQ) effect corresponding to the nanocarbon without embedded defect. Incorporating pore defects into chiral nanocarbon molecules also simplifies the synthesis process and enhances the solubility of the resulting product. These findings suggest that the introduction of pore defects can be a viable approach to improve nanocarbon molecules.

Analysis of the Economic Burden of Chronic Kidney Disease With Comorbidities Among Patients in Xuzhou, China.

Objectives: To analyze the costs and medication patterns of patients with chronic kidney disease (CKD) and comorbidities in Xuzhou, China, using a large electronic medical records database. Methods: Data were obtained from an electronic medical records database. The annual per-person and per-visit cost of hospitalization, as well as the proportions of those costs, are presented. Results: The majority of the participants were middle-aged men, and had medical insurance. Glomerulonephritis was the primary cause of CKD in patients with an identified etiology. The average per-visit cost of hospitalization for the CKD-renal anemia and CKD-mineral and bone disorder groups was 8,674.5 (5,154.3-13,949.6) and 8,182.6 (4,798.2-12,844.7) Yuan, respectively, which was greater than that of the other groups. The major expenses incurred were for diagnostics, drug usage, surgical procedures, laboratory tests and material costs. Conclusion: The substantial burden imposed by CKD with comorbidities indicates the importance of implementing public health strategies aimed at detecting and preventing these conditions in the general population. With the aging population, our nation may experience a greater CKD-related economic burden.

Association between the anion-gap and 28-day mortality in critically ill adult patients with sepsis: A retrospective cohort study.

Metabolic acidosis is usually associated with the severity of the condition of patients with sepsis or septic shock. Serum anion gap (AG) is one of the indicators of response metabolism. This study was performed to investigate whether the initial serum AG is associated with the 28-day mortality in critically ill adult patients with sepsis. This retrospective cohort study, a total of 15,047 patients with confirmed Sepsis disease from 2008 to 2019 from the Medical Information Mart for Intensive Care IV (MIMIC-IV) v1.0 database. The MIMIC-IV database is a comprehensive, de-identified clinical dataset originating from the Beth Israel Deaconess Medical Center in Boston, it includes extensive data on intensive care unit (ICU) patients, such as vital signs, lab results, and medication orders, spanning multiple years, accessible to researchers through an application process. AG can be obtained by direct extraction in the MIMIC-IV database (itemid = 50,868 from the laboratory events table of mimic_hosp), inclusion of AG values for the first test on first day of ICU admission. The patients were grouped into quartiles according to the AG interquartile range. The primary outcome was the 28-day mortality. Multiple logistic regression analysis was used to calculate the odds ratio (OR), while accounting for potential confounders, and the robustness of the results were evaluated in subgroup analyses. Among the 15,047 patients included in this study, the average age was 65.9 ±â€…16.0 years, 42.5% were female, 66.1% were Caucasian, and the 28-day mortality rate was 17.9% (2686/15,047). Multiple logistic regression analysis revealed the 28-day mortality in every increase of AG (per SD mEq/L), there is an associated 1.2 times (OR 1.2, 95% CI 1.12-1.29, P < .001) increase. Increased 28-day mortality (OR 1.53, 95% confidence interval 1.29-1.81, P < .001) in the group with the AG (15-18 mEq/L), and (OR 1.69, 95% confidence interval 1.4-2.04, P < .001) in the group with the highest AG (≥18 mEq/L), AG (<12 mEq/L) as a reference group, in the fully adjusted model. In adult patients with sepsis, the early AG at the time of ICU admission is an independent risk factor for prognosis.

Hepatitis B virus infection during pregnancy and the risk of postpartum hemorrhage: a protocol for systematic review and meta-analysis.

Background: Hepatitis B virus (HBV) infection is a significant public health issue worldwide, with a hepatitis B surface antigen (HBsAg) seroprevalence of 3.5%. Maternal HBV infection during pregnancy, a common comorbidity, is associated with an increase in the risk of adverse obstetric and perinatal outcomes. However, the relationship between maternal HBV infection and postpartum hemorrhage (PPH), a leading contributor to maternal morbidity and mortality, is currently uncertain. The aim of this study is to comprehensively clarify the potential impact of maternal HBV on PPH risk. Methods and Analysis: The authors initially searched five English databases and three Chinese databases from their inception to 26th June 2023. Two reviewers will independently conduct study selection, data extraction, and quality assessment. Cohort and case-control studies investigating the effect of maternal HBV infection on PPH will be included, with study quality assessed using the Newcastle-Ottawa Scale (NOS). Meta-analyses will be performed using a fixed-effects model for I 2≤50% or a random-effects model otherwise. Several categories of subgroup analyses (e.g. sample size more than 1000 vs. less than 1000) and sensitivity analyses (e.g. omit NOS scores less than 7) will be conducted, and publication bias will be assessed through funnel plots, Begg's and Egger's tests using STATA 18.0. Ethics and Dissemination: This systematic review and meta-analysis do not require ethics approval and the results will be published in peer-reviewed journals. The findings of this systematic review will provide evidence on the impact of maternal HBV infection on PPH, which will contribute to better prevention and management of PPH in clinical practice and a better understanding of the disease burden of HBV infection. PROSPERO registration number: CRD42023442626.

Lacticaseibacillus paracasei LC86 mitigates age-related muscle wasting and cognitive impairment in SAMP8 mice through gut microbiota modulation and the regulation of serum inflammatory factors.

Purpose: Chronic inflammation contributes to the decline in muscle strength and cognitive abilities associated with aging. This study aims to clarify the effects of oral administration of Lacticaseibacillus paracasei LC86 on these age-related declines, as well as its impact on the composition of gut microbiota. Methods: Senescence-accelerated mouse prone 8 (SAMP8) mice received a 12 week regimen of LC86 (1 × 109 CFU/day). Muscle strength was assessed through forelimb grip strength and four-limb hanging tests. Cognitive function was evaluated through behavioral performance tests, and changes in gut microbiota were analyzed. Results: Administration of LC86 significantly enhanced muscle strength, demonstrated by increased grip strength and higher glycogen content in the gastrocnemius muscle (p = 0.041, p = 0.017, and p = 0.000, respectively). Behavioral tests suggested that LC86 mitigated age-related cognitive decline. Furthermore, there was a significant decrease in serum pro-inflammatory cytokines, such as IL-6, TNF-α, and MCP-1 (p = 0.002, p = 0.000, and p = 0.005, respectively), and an elevation in the anti-inflammatory cytokine IL-10 level (p = 0.000). An increase in hepatic antioxidant capacity was observed. Significant changes in the gut microbiota composition were noted, including increased populations of Bifidobacterium and Lactobacillus and decreased levels of Escherichia/Shigella and Bacteroides. Conclusion: The findings suggest that LC86 supplementation mitigates muscle weakness and cognitive impairment in aging SAMP8 mice, potentially through the modulation of inflammation and gut microbiota composition. LC86 emerges as a promising candidate for ameliorating the decline of muscular and cognitive functions associated with aging.

Adaptive designs were primarily used but inadequately reported in early phase drug trials.

BACKGROUND: Faced with the high cost and limited efficiency of classical randomized controlled trials, researchers are increasingly applying adaptive designs to speed up the development of new drugs. However, the application of adaptive design to drug randomized controlled trials (RCTs) and whether the reporting is adequate are unclear. Thus, this study aimed to summarize the epidemiological characteristics of the relevant trials and assess their reporting quality by the Adaptive designs CONSORT Extension (ACE) checklist. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception to January 2020. We included drug RCTs that explicitly claimed to be adaptive trials or used any type of adaptative design. We extracted the epidemiological characteristics of included studies to summarize their adaptive design application. We assessed the reporting quality of the trials by Adaptive designs CONSORT Extension (ACE) checklist. Univariable and multivariable linear regression models were used to the association of four prespecified factors with the quality of reporting. RESULTS: Our survey included 108 adaptive trials. We found that adaptive design has been increasingly applied over the years, and was commonly used in phase II trials (n = 45, 41.7%). The primary reasons for using adaptive design were to speed the trial and facilitate decision-making (n = 24, 22.2%), maximize the benefit of participants (n = 21, 19.4%), and reduce the total sample size (n = 15, 13.9%). Group sequential design (n = 63, 58.3%) was the most frequently applied method, followed by adaptive randomization design (n = 26, 24.1%), and adaptive dose-finding design (n = 24, 22.2%). The proportion of adherence to the ACE checklist of 26 topics ranged from 7.4 to 99.1%, with eight topics being adequately reported (i.e., level of adherence ≥ 80%), and eight others being poorly reported (i.e., level of adherence ≤ 30%). In addition, among the seven items specific for adaptive trials, three were poorly reported: accessibility to statistical analysis plan (n = 8, 7.4%), measures for confidentiality (n = 14, 13.0%), and assessments of similarity between interim stages (n = 25, 23.1%). The mean score of the ACE checklist was 13.9 (standard deviation [SD], 3.5) out of 26. According to our multivariable regression analysis, later published trials (estimated ß = 0.14, p < 0.01) and the multicenter trials (estimated ß = 2.22, p < 0.01) were associated with better reporting. CONCLUSION: Adaptive design has shown an increasing use over the years, and was primarily applied to early phase drug trials. However, the reporting quality of adaptive trials is suboptimal, and substantial efforts are needed to improve the reporting.

Blood Urine Nitrogen Trajectories of Acute Pancreatitis Patients in Intensive Care Units.

Objective: To identify subclasses of acute pancreatitis (AP) patients in the intensive care unit (ICU) by analyzing blood urea nitrogen (BUN) trajectories. Methods: AP patients in West China Hospital System (development cohort) and three public databases in the United States (validation cohort) were included. Latent class trajectory modelling was used to identify subclasses based on BUN trajectories within the first 21 days after ICU admission. Clinical characteristics and outcomes were compared, and results were externally validated. Results: The study comprised 2971 and 930 patients in the development and validation cohorts, respectively, with five subclasses: Class 1 ("Moderate-azotemia, slow decreasing"), Class 2 ("Non-azotemia"), Class 3 ("Severe-azotemia, slow decreasing"), Class 4 ("Moderate-azotemia, rapid increasing"), and Class 5 ('Moderate-azotemia, slow increasing) identified. Azotemia patients showed significantly higher 30-day mortality risk in development and validation cohorts. Specifically, Class 4 patients exhibited notably highest mortality risk in both the development cohort (HR 5.32, 95% CI 2.62-10.82) and validation cohort (HR 6.23, 95% CI 2.93-13.22). Regarding clinical characteristics, AP patients in Class 4 showed lower mean arterial pressure and a higher proportion of renal disease. We also created an online early classification model to further identify Class 4 patients among all patients with moderate azotemia at baseline. Conclusion: This multinational study uncovers heterogeneity in BUN trajectories among AP patients. Patients with "Moderate-azotemia, rapid increasing" trajectory, had a higher mortality risk than patients with severe azotemia at baseline. This finding complements studies that solely rely on baseline BUN for risk stratification and enhanced our understanding of longitudinal progression of AP.

Reduction in Serum Concentrations of Uremic Toxins Driven by Bifidobacterium Longum Subsp. Longum BL21 is Associated with Gut Microbiota Changes in a Rat Model of Chronic Kidney Disease.

Gut microbiota dysbiosis and consequent impairment of gut barrier function, culminating in elevated levels of uremic toxins, are prevalent in chronic kidney disease (CKD) patients. These toxins, notably indoxyl sulphate (IS), indole-3-acetic acid (IAA), and trimethylamine oxide (TMAO), are implicated in a spectrum of CKD-related complications, including cardiovascular disease, bone and mineral disorders, and inflammation. The specific impacts of various probiotics on these CKD manifestations remain unexplored. This study delved into the potential of dietary probiotic interventions, particularly Bifidobacterium longum subsp. longum BL21, to modulate gut microbiota and mitigate metabolic disorders in a CKD rat model. Over a six-week period, we administered a dietary regimen of BL21 and conducted comprehensive analyses, including serum uremic toxin quantification and 16S rRNA gene sequencing, to systematically profile gut microbial alterations at the phylogenetic level. Our findings reveal that BL21 intervention significantly ameliorated CKD-induced disruptions in gut microbial populations, enhancing both microbial richness and the relative abundance of key taxa. Importantly, BL21 appeared to exert its beneficial effects by modulating the abundance of crucial species such as Barnesiella and Helicobacter. Functionally, the intervention markedly normalized serum levels of IS, IAA, and TMAO, while potentially attenuating p-cresol sulphate (PCS) and p-cresol glucuronide (PCG) concentrations. Consequently, BL21 demonstrated efficacy in regulating gut microbiota and curtailing the accumulation of uremic toxins. Our results advocate for the utilization of BL21 as a dietary intervention to diminish serum uremic toxins and re-establish gut microbiota equilibrium at the phylogenetic level, underscoring the promise of probiotic strategies in the management of CKD.

Development and validation of a nomogram for predicting in-hospital mortality of intensive care unit patients with liver cirrhosis.

BACKGROUND: Liver cirrhosis patients admitted to intensive care unit (ICU) have a high mortality rate. AIM: To establish and validate a nomogram for predicting in-hospital mortality of ICU patients with liver cirrhosis. METHODS: We extracted demographic, etiological, vital sign, laboratory test, comorbidity, complication, treatment, and severity score data of liver cirrhosis patients from the Medical Information Mart for Intensive Care IV (MIMIC-IV) and electronic ICU (eICU) collaborative research database (eICU-CRD). Predictor selection and model building were based on the MIMIC-IV dataset. The variables selected through least absolute shrinkage and selection operator analysis were further screened through multivariate regression analysis to obtain final predictors. The final predictors were included in the multivariate logistic regression model, which was used to construct a nomogram. Finally, we conducted external validation using the eICU-CRD. The area under the receiver operating characteristic curve (AUC), decision curve, and calibration curve were used to assess the efficacy of the models. RESULTS: Risk factors, including the mean respiratory rate, mean systolic blood pressure, mean heart rate, white blood cells, international normalized ratio, total bilirubin, age, invasive ventilation, vasopressor use, maximum stage of acute kidney injury, and sequential organ failure assessment score, were included in the multivariate logistic regression. The model achieved AUCs of 0.864 and 0.808 in the MIMIC-IV and eICU-CRD databases, respectively. The calibration curve also confirmed the predictive ability of the model, while the decision curve confirmed its clinical value. CONCLUSION: The nomogram has high accuracy in predicting in-hospital mortality. Improving the included predictors may help improve the prognosis of patients.

Global study of anti-NMDA encephalitis: a bibliometric analysis from 2005 to 2023.

Background: Autoimmune diseases have always been one of the difficult diseases of clinical concern. Because of the diversity and complexity of its causative factors, unclear occurrence and development process and difficult treatment, it has become a key disease for researchers to study. And the disease explored in this paper, anti-NMDA encephalitis, belongs to a common type of autoimmune encephalitis. However, the quality of articles and research hotspots in this field are not yet known. Therefore, in this field, we completed a bibliometric and visualization analysis from 2005 to 2023 in order to understand the research hotspots and directions of development in this field. Materials and methods: We searched the SCI-expanded databases using Web of Science's core databases on January 22, 2024 and used tools such as VOS viewer, Cite Space, and R software to visualize and analyze the authors, countries, journals, institutions, and keywords of the articles. Results: A total of 1,161 literatures were retrieved and analyzed in this study. China was the country with the most total publications, and USA and Spain were the most influential countries in the field of anti-NMDA encephalitis. University of Pennsylvania from USA was the institution with the highest number of publications. While Dalmau Josep is the most prolific, influential and contributing author who published one of the most cited articles in Lancet Neurology, which laid the foundation for anti-NMDA encephalitis research, the top three appearances of keyword analysis were: "antibodies", "diagnosis", and "autoimmune encephalitis." Conclusion: Bibliometric analysis shows that the number of studies on anti-NMDA encephalitis is generally increasing year by year, and it is a hot disease pursued by researchers. USA and Spain are leading in the field of anti-NMDA encephalitis, while China should continue to improve the quality of its own research. The suspected causes of anti-NMDA encephalitis other than ovarian teratoma and herpes simplex, the specific clinical manifestations that are not masked by psychiatric symptoms, the diagnostic modalities that are faster and more accurate than antibody tests, and the improvement of treatment modalities by evaluating prognosis of various types of patients are the hotspots for future research.

Research hotspots and evolving trends of barrier dysfunction in acute lung injury and acute respiratory distress syndrome.

Endothelial and epithelial barrier dysfunction due to increased permeability and heightened inflammatory reactions influences the emergence of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Nevertheless, bibliometric research comparing endothelial and epithelial barriers is limited. Therefore, this bibliometric study analyzed the Web of Science Core Collection (WoSCC) of the Science Citation Index Expanded literature to explore present research priorities and development tendencies within this field. We conducted a comprehensive search (October 18, 2023) on WoSCC from January 1, 2010, to October 18, 2023, focusing on articles related to endothelial and epithelial barriers in ALI and ARDS. Retrieved data were visualized and analyzed using R-bibliometrix, VOS viewer 1.6.19, and CiteSpace 6.2. R4. Functional enrichment analysis of gene targets identified in the keyword list using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene ontology databases, and based on the STRING database to construct a PPI network to predict core genes. A total of 941 original articles and reviews were identified. The United States had the highest number of publications and citations and the highest H-index and G-index. According to the Collaboration Network Analysis graph, the United States and China had the strongest collaboration. Birukova AA had the most publications and citations among all authors, while eight of the top ten institutions with mediator centrality were located in the United States. The American Journal of Physiology-Lung Cellular and Molecular Physiology was the leading journal and had the most well-established publication on endothelial and epithelial barriers in ALI and ARDS. Bibliometric analysis revealed that the most frequently used keywords were acute lung injury, ARDS, activation, expression, and inflammation. RHOA appeared most frequently among gene-related keywords, and the PI3K-AKT signaling pathway had the highest count in KEGG pathway enrichment. Research on endothelial versus epithelial barriers in ALI and ARDS remains preliminary. This bibliometric study examined cooperative network connections among countries, authors, journals, and network associations in the cited references. Investigation of the functions of the endothelial and epithelial barriers in ALI/ARDS associated with COVID-19 has recently gained significant attention.