In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer.

Improving effector activity of antigen-specific T cells is a major goal in cancer immunotherapy. Despite the identification of several effector T cell (TEFF)-driving transcription factors (TFs), the transcriptional coordination of TEFF biology remains poorly understood. We developed an in vivo T cell CRISPR screening platform and identified a key mechanism restraining TEFF biology through the ETS family TF, Fli1. Genetic deletion of Fli1 enhanced TEFF responses without compromising memory or exhaustion precursors. Fli1 restrained TEFF lineage differentiation by binding to cis-regulatory elements of effector-associated genes. Loss of Fli1 increased chromatin accessibility at ETS:RUNX motifs, allowing more efficient Runx3-driven TEFF biology. CD8+ T cells lacking Fli1 provided substantially better protection against multiple infections and tumors. These data indicate that Fli1 safeguards the developing CD8+ T cell transcriptional landscape from excessive ETS:RUNX-driven TEFF cell differentiation. Moreover, genetic deletion of Fli1 improves TEFF differentiation and protective immunity in infections and cancer.

Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation.

Exhausted CD8 T cells (TEX) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate TEX cells, but reinvigoration is not durable. A major unanswered question is whether TEX cells differentiate into functional durable memory T cells (TMEM) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, TEX cells partially (re)acquire phenotypic and transcriptional features of TMEM cells. These 'recovering' TEX cells originated from the T cell factor (TCF-1+) TEX progenitor subset. Nevertheless, the recall capacity of these recovering TEX cells remained compromised as compared to TMEM cells. Chromatin-accessibility profiling revealed a failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for TEX cell-targeted immunotherapies.

MicroRNA-29a attenuates CD8 T cell exhaustion and induces memory-like CD8 T cells during chronic infection.

CD8 T cells mediate protection against intracellular pathogens and tumors. However, persistent antigen during chronic infections or cancer leads to T cell exhaustion, suboptimal functionality, and reduced protective capacity. Despite considerable work interrogating the transcriptional regulation of exhausted CD8 T cells (TEX), the posttranscriptional control of TEX remains poorly understood. Here, we interrogated the role of microRNAs (miRs) in CD8 T cells responding to acutely resolved or chronic viral infection and identified miR-29a as a key regulator of TEX. Enforced expression of miR-29a improved CD8 T cell responses during chronic viral infection and antagonized exhaustion. miR-29a inhibited exhaustion-driving transcriptional pathways, including inflammatory and T cell receptor signaling, and regulated ribosomal biogenesis. As a result, miR-29a fostered a memory-like CD8 T cell differentiation state during chronic infection. Thus, we identify miR-29a as a key regulator of TEX and define mechanisms by which miR-29a can divert exhaustion toward a more beneficial memory-like CD8 T cell differentiation state.

Effect of a multicomponent quality improvement strategy on sustained achievement of diabetes care goals and macrovascular and microvascular complications in South Asia at 6.5 years follow-up: Post hoc analyses of the CARRS randomized clinical trial.

BACKGROUND: Diabetes control is poor globally and leads to burdensome microvascular and macrovascular complications. We aimed to assess post hoc between-group differences in sustained risk factor control and macrovascular and microvascular endpoints at 6.5 years in the Center for cArdiovascular Risk Reduction in South Asia (CARRS) randomized trial. METHODS AND FINDINGS: This parallel group individual randomized clinical trial was performed at 10 outpatient diabetes clinics in India and Pakistan from January 2011 through September 2019. A total of 1,146 patients with poorly controlled type 2 diabetes (HbA1c ≥8% and systolic BP ≥140 mm Hg and/or LDL-cholesterol ≥130 mg/dL) were randomized to a multicomponent quality improvement (QI) strategy (trained nonphysician care coordinator to facilitate care for patients and clinical decision support system for physicians) or usual care. At 2.5 years, compared to usual care, those receiving the QI strategy were significantly more likely to achieve multiple risk factor control. Six clinics continued, while 4 clinics discontinued implementing the QI strategy for an additional 4-year follow-up (overall median 6.5 years follow-up). In this post hoc analysis, using intention-to-treat, we examined between-group differences in multiple risk factor control (HbA1c <7% plus BP <130/80 mm Hg and/or LDL-cholesterol <100 mg/dL) and first macrovascular endpoints (nonfatal myocardial infarction, nonfatal stroke, death, revascularization [angioplasty or coronary artery bypass graft]), which were co-primary outcomes. We also examined secondary outcomes, namely, single risk factor control, first microvascular endpoints (retinopathy, nephropathy, neuropathy), and composite first macrovascular plus microvascular events (which also included amputation and all-cause mortality) by treatment group and whether QI strategy implementation was continued over 6.5 years. At 6.5 years, assessment data were available for 854 participants (74.5%; n = 417 [intervention]; n = 437 [usual care]). In terms of sociodemographic and clinical characteristics, participants in the intervention and usual care groups were similar and participants at sites that continued were no different to participants at sites that discontinued intervention implementation. Patients in the intervention arm were more likely to exhibit sustained multiple risk factor control than usual care (relative risk: 1.77; 95% confidence interval [CI], 1.45, 2.16), p < 0.001. Cumulatively, there were 233 (40.5%) first microvascular and macrovascular events in intervention and 274 (48.0%) in usual care patients (absolute risk reduction: 7.5% [95% CI: -13.2, -1.7], p = 0.01; hazard ratio [HR] = 0.72 [95% CI: 0.61, 0.86]), p < 0.001. Patients in the intervention arm experienced lower incidence of first microvascular endpoints (HR = 0.68 [95% CI: 0.56, 0.83), p < 0.001, but there was no evidence of between-group differences in first macrovascular events. Beneficial effects on microvascular and composite vascular outcomes were observed in sites that continued, but not sites that discontinued the intervention. CONCLUSIONS: In urban South Asian clinics, a multicomponent QI strategy led to sustained multiple risk factor control and between-group differences in microvascular, but not macrovascular, endpoints. Between-group reductions in vascular outcomes at 6.5 years were observed only at sites that continued the QI intervention, suggesting that practice change needs to be maintained for better population health of people with diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01212328.

Improving health outcomes of people with diabetes: target setting for the WHO Global Diabetes Compact.

The Global Diabetes Compact is a WHO-driven initiative uniting stakeholders around goals of reducing diabetes risk and ensuring that people with diabetes have equitable access to comprehensive, affordable care and prevention. In this report we describe the development and scientific basis for key health metrics, coverage, and treatment targets accompanying the Compact. We considered metrics across four domains: factors at a structural, system, or policy level; processes of care; behaviours and biomarkers such as glycated haemoglobin (HbA1c); and health events and outcomes; and three risk tiers (diagnosed diabetes, high risk, or whole population), and reviewed and prioritised them according to their health importance, modifiability, data availability, and global inequality. We reviewed the global distribution of each metric to set targets for future attainment. This process led to five core national metrics and target levels for UN member states: (1) of all people with diabetes, at least 80% have been clinically diagnosed; and, for people with diagnosed diabetes, (2) 80% have HbA1c concentrations below 8·0% (63·9 mmol/mol); (3) 80% have blood pressure lower than 140/90 mm Hg; (4) at least 60% of people 40 years or older are receiving therapy with statins; and (5) each person with type 1 diabetes has continuous access to insulin, blood glucose meters, and test strips. We also propose several complementary metrics that currently have limited global coverage, but warrant scale-up in population-based surveillance systems. These include estimation of cause-specific mortality, and incidence of end-stage kidney disease, lower-extremity amputations, and incidence of diabetes. Primary prevention of diabetes and integrated care to prevent long-term complications remain important areas for the development of new metrics and targets. These metrics and targets are intended to drive multisectoral action applied to individuals, health systems, policies, and national health-care access to achieve the goals of the Global Diabetes Compact. Although ambitious, their achievement can result in broad health benefits for people with diabetes.

Induced genetic diversity through mutagenesis in wheat gene pool and significant use of SCoT markers to underpin key agronomic traits.

BACKGROUND: This research explores the efficacy of mutagenesis, specifically using sodium azide (SA) and hydrazine hydrate (HZ) treatments, to introduce genetic diversity and enhance traits in three wheat (Triticum aestivum L.) genotypes. The experiment entails subjecting the seeds to different doses of SA and HZ and cultivating them in the field for two consecutive generations: M1 (first generation) and M2 (second generation). We then employed selective breeding techniques with Start Codon Targeted (SCoT) markers to select traits within the wheat gene pool. Also, the correlation between SCoT markers and specific agronomic traits provides insights into the genetic mechanisms underlying mutagenesis-induced changes in wheat. RESULTS: In the study, eleven genotypes were derived from parent varieties Sids1, Sids12, and Giza 168, and eight mutant genotypes were selected from the M1 generation and further cultivated to establish the M2 generation. The results revealed that various morphological and agronomical characteristics, such as plant height, spikes per plant, spike length, spikelet per spike, grains per spikelet, and 100-grain weight, showed increases in different genotypes from M1 to M2. SCoT markers were employed to assess genetic diversity among the eleven genotypes. The bioinformatics analysis identified a correlation between SCoT markers and the transcription factors ABSCISIC ACID INSENSITIVE3 (ABI3) and VIVIPAROUS1 (VP1), crucial for plant development, growth, and stress adaptation. A comprehensive examination of genetic distance and the function identification of gene-associated SCoT markers may provide valuable insights into the mechanisms by which SA and HZ act as mutagens, enhancing wheat agronomic qualities. CONCLUSIONS: This study demonstrates the effective use of SA and HZ treatments to induce gene diversity through mutagenesis in the wheat gene pool, resulting in the enhancement of agronomic traits, as revealed by SCoT markers. The significant improvements in morphological and agronomical characteristics highlight the potential of mutagenesis techniques for crop improvement. These findings offer valuable information for breeders to develop effective breeding programs to enhance wheat quality and resilience through increased genetic diversity.

Is Electronic Information Exchange Associated With Lower 30-Day Readmission Charges Among Medicare Beneficiaries?

OBJECTIVE: Fragmented readmissions, when admission and readmission occur at different hospitals, are associated with increased charges compared with nonfragmented readmissions. We assessed if hospital participation in health information exchange (HIE) was associated with differences in total charges in fragmented readmissions. DATA SOURCE: Medicare Fee-for-Service Data, 2018. STUDY DESIGN: We used generalized linear models with hospital referral region and readmission month fixed effects to assess relationships between information sharing (same HIE, different HIEs, and no HIE available) and total charges of 30-day readmissions among fragmented readmissions; analyses were adjusted for patient-level clinical/demographic characteristics and hospital-level characteristics. DATA EXTRACTION METHODS: We included beneficiaries with a hospitalization for acute myocardial infarction, congestive heart failure, chronic obstructive pulmonary disease, syncope, urinary tract infection, dehydration, or behavioral issues with a 30-day readmission for any reason. PRINCIPAL FINDINGS: In all, 279,729 admission-readmission pairs were included, 27% of which were fragmented (n=75,438); average charges of fragmented readmissions were $64,897-$71,606. Compared with fragmented readmissions where no HIE was available, the average marginal effects of same-HIE and different-HIE admission-readmission pairs were -$2329.55 (95% CI: -7333.73, 2674.62) and -$3905.20 (95% CI: -7592.85, -307.54), respectively. While the average marginal effects of different-HIE pairs were lower than those for no-HIE fragmented readmissions, the average marginal effects of same-HIE and different-HIE pairs were not significantly different from each other. CONCLUSIONS: There were no statistical differences in charges between fragmented readmissions to hospitals that share an HIE or that do not share an HIE compared with hospitals with no HIE available.

Factors influencing diabetes treatment satisfaction in the INtegrating DEPrEssioN and Diabetes treatmENT randomized clinical trial: A multilevel model analysis.

AIMS: Patient satisfaction is associated with positive diabetes outcomes. However, there are no identified studies that evaluate both patient- and clinic-level predictors influencing diabetes care satisfaction longitudinally. METHODS: Data from the INtegrating DEPrEssioN and Diabetes treatmENT trial was used to perform the analysis. We used fixed and random effects models to assess whether and how changes in patient-level predictors (treatment assignment, depression symptom severity, systolic blood pressure, body mass index, LDL cholesterol, and haemoglobin A1C) from 0 to 24 months and clinic-level predictors (visit frequency, visit cost, number of specialists, wait time, time spent with healthcare provider, and receiving verbal reminders) measured at 24 months influence diabetes care satisfaction from 0 to 24 months. RESULTS: Model 1 (patient-level predictors) accounted for 7% of the change in diabetes satisfaction and there was a significant negative relationship between change in depressive symptoms and care satisfaction (ß = -0.23, SE = 0.12, p < 0.05). Within Model 1, 2% of the variance was explained by clinic-level predictors. Model 2 included both patient- and clinic-level predictors and accounted for 18% of the change in diabetes care satisfaction. Within Model 2, 9% of the variance was attributed to clinic-level predictors. There was also a cross-level interaction where the change in depression had less of an impact on the change in satisfaction for those who received a verbal reminder (ß = -0.11, SE = 0.21, p = 0.34) compared with those who did not receive a reminder (ß = -0.62, SE = 0.08, p < 0.01). CONCLUSIONS: Increased burden of depressive symptoms influences diabetes care satisfaction. Clinic-level predictors also significantly influence diabetes care satisfaction and can reduce dissatisfaction in primary care, specifically, reminder calls from clinic staff.

Electrochemical C-H/C-C Bond Oxygenation: A Potential Technology for Plastic Depolymerization.

Herein, we provide eco-friendly and safely operated electrocatalytic methods for the selective oxidation directly or with water, air, light, metal catalyst or other mediators serving as the only oxygen supply. Heavy metals, stoichiometric chemical oxidants, or harsh conditions were drawbacks of earlier oxidative cleavage techniques. It has recently come to light that a crucial stage in the deconstruction of plastic waste and the utilization of biomass is the selective activation of inert C(sp3 )-C/H(sp3 ) bonds, which continues to be a significant obstacle in the chemical upcycling of resistant polyolefin waste. An appealing alternative to chemical oxidations using oxygen and catalysts is direct or indirect electrochemical conversion. An essential transition in the chemical and pharmaceutical industries is the electrochemical oxidation of C-H/C-C bonds. In this review, we discuss cutting-edge approaches to chemically recycle commercial plastics and feasible C-C/C-H bonds oxygenation routes for industrial scale-up.

5-Year simulation of diabetes-related complications in people treated with tirzepatide or semaglutide versus insulin glargine.

AIM: This study compared the 5-year incidence rate of macrovascular and microvascular complications for tirzepatide, semaglutide and insulin glargine in individuals with type 2 diabetes, using the Building, Relating, Assessing, and Validating Outcomes (BRAVO) diabetes simulation model. RESEARCH DESIGN AND METHODS: This study was a 5-year SURPASS-2 trial extrapolation, with an insulin glargine arm added as an additional comparator. The 1-year treatment effects of tirzepatide (5, 10 or 15 mg), semaglutide (1 mg) and insulin glargine on glycated haemoglobin, systolic blood pressure, low-density lipoprotein and body weights were obtained from the SUSTAIN-4 and SURPASS-2 trials. We used the BRAVO model to predict 5-year complications for each study arm under two scenarios: the 1-year treatment effects persisted (optimistic) or diminished to none in 5 years (conservative). RESULTS: When compared with insulin glargine, we projected a 5-year risk reduction in cardiovascular adverse events [rate ratio (RR) 0.64, 95% confidence interval (CI) 0.61-0.67] and microvascular composite (RR 0.67, 95% CI 0.64-0.70) with 15 mg tirzepatide, and 5-year risk reduction in cardiovascular adverse events (RR 0.75, 95% CI 0.72-0.79) and microvascular composite (RR 0.79, 95% CI 0.76-0.82) with semaglutide (1 mg) under an optimistic scenario. Lower doses of tirzepatide also had similar, albeit smaller benefits. Treatment effects for tirzepatide and semaglutide were smaller but still significantly higher than insulin glargine under a conservative scenario. The 5-year risk reduction in diabetes-related complication events and mortality for the 15 mg tirzepatide compared with insulin glargine ranged from 49% to 10% under an optimistic scenario, which was reduced by 17%-33% when a conservative scenario was assumed. CONCLUSION: With the use of the BRAVO diabetes model, tirzepatide and semaglutide exhibited potential to reduce the risk of macrovascular and microvascular complications among individuals with type 2 diabetes, compared with insulin glargine in a 5-year window. Based on the current modelling assumptions, tirzepatide (15 mg) may potentially outperform semaglutide (1 mg). While the BRAVO model offered insights, the long-term cardiovascular benefit of tirzepatide should be further validated in a prospective clinical trial.

Renal function as an effect modifier of intensive glucose control in delaying cognitive function decline among individuals with type 2 diabetes: A revisit to the ACCORD MIND trial.

AIM: Dysglycaemia accelerates cognitive decline. Intensive glucose control may help delay or prevent cognitive function decline (CFD). We aimed to determine how patient characteristics influence the effect of intensive glucose control [glycated haemoglobin (HbA1c) <6.0%] on delaying CFD in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this post-hoc analysis of 2977 type 2 diabetes participants from the ACCORD MIND trial, we applied the causal forest and causal tree algorithms to identify the effect modifier of intensive glucose control in delaying CFD from 68 variables (demographics, disease history, medications, vitals and baseline biomarkers). The exposure was intensive versus standard glucose control (HbA1c <6.0% vs. 7.0%-7.9%). The main outcome was cognitive function changes from baseline to the 40th month follow-up, which were evaluated using the digit symbol substitution test, Rey auditory verbal learning test, mini-mental state examination and Stroop test. We used Cohen's d, a measure of standardized difference, to quantify the effect size of intensive glucose control on delaying CFD. RESULTS: Among all the baseline characteristics, renal function was the most significant effect modifier. Participants with urinary albumin levels <0.4 mg/dl [absolute function change (AFC): 0.51 in mini-mental state examination, 95% confidence interval (CI): 0.04, 0.98, Cohen's d: 0.25] had slower CFD with intensive glucose control. Patients with preserved renal function (estimated glomerular filtration rate between 60 and 90 ml/min/1.73 m2) were associated with small benefits (AFC: 1.28 in Stroop, 95% CI: 0.28, 2.27, Cohen's d: 0.12) when undergoing intensive glucose control. Conversely, participants with an estimated glomerular filtration rate <60 ml/min/1.73 m2 (AFC: -0.57 in the Rey auditory verbal learning test, 95% CI: -1.09, -0.05, Cohen's d: -0.30) exhibited faster CFD when undergoing intensive glucose control. Participants who were <60 years old showed a significant benefit from intensive glucose control in delaying CFD (AFC: 1.08 in the digit symbol substitution test, 95% CI: 0.06, 2.10, Cohen's d: 0.13). All p < .05. CONCLUSIONS: Our findings linked renal function with the benefits of intensive glucose control in delaying CFD, informing personalized HbA1c goals for those with diabetes and at risk of CFD.

Association between low cognitive performance and diabetes-related health indicators across racial and ethnic groups in adults with diabetes.

AIM: To examine the associations between low cognitive performance (LCP) and diabetes-related health indicators (including body mass index [BMI], HbA1c, systolic blood pressure [SBP], low-density lipoprotein [LDL] and self-reported poor physical health) and whether these associations vary across racial/ethnic subgroups. METHODS: We identified adults aged 60 years or older with self-reported diabetes from the 2011-2014 National Health and Nutrition Examination Survey. Individuals with cognitive test scores in the lowest quartile were defined as having LCP. We used regression models to measure the associations of LCP with diabetes-related biometrics (BMI, HbA1c, SBP and LDL); and self-reported poor physical health. Moreover, we explored potential variations in these associations across racial/ethnic subgroups. RESULTS: Of 873 (261 with LCP) adults with diabetes, LCP was associated with higher HbA1c, SBP and LDL (adjusted difference: 0.41%, 5.01 mmHg and 5.08 mg/dL, respectively; P < .05), and greater odds of reporting poor physical health (adjusted odds ratio: 1.59, P < .05). The association between LCP and HbA1c was consistent across racial/ethnic groups, and notably pronounced in Hispanic and Other. BMI worsened with LCP, except for non-Hispanic Black. Excluding the Other group, elevated SBP was observed in people with LCP, with Hispanic showing the most significant association. LDL levels were elevated with LCP for Hispanic and Other. Physical health worsened with LCP for both non-Hispanic Black and Hispanic. CONCLUSIONS: We quantified the association between LCP and diabetes-related health indicators. These associations were more pronounced in Hispanic and Other racial/ethnic groups.

Possible Role of Netrin-1/Deleted in Colorectal Cancer/Vascular Endothelial Growth Factor Signaling Pathway in the Pathogenesis of Placenta Accreta Spectrum: A Case-control Study.

SUMMARY: Netrin-1, an epithelial-secreted protein, plays a key role in placental formation through the promotion of cytotrophoblast proliferation and placental vascular development. These effects are mediated through several receptors, including the deleted in colorectal cancer (DCC) receptor. Placenta accreta spectrum (PAS) is an exaggerated trophoblastic invasion into the uterine myometrium. The exact etiology is unknown, but it is believed that increased trophoblastic invasion, defect decidualization, and/or abnormal angiogenesis might play a role. Our study aimed to investigate the suggested role of macrophage-induced netrin-1/DCC/vascular endothelial growth factor (VEGF) signaling in PAS pathogenesis. A total of 29 women with PAS (as cases) and 29 women with normal pregnancies (as controls) were enrolled in the study. At delivery, placental tissues of both groups were collected and processed for the evaluation of placental netrin-1 level by enzyme-linked immunoassay technique and immunohistochemical analysis of tissue DCC receptor. Placental tissue netrin-1 level of PAS cases showed a statistically significantly higher value than those in the normal group. Significant overexpression of DCC receptors, VEGF, and enhanced macrophage recruitment was noted in PAS cases in comparison to the normal placenta. Macrophage-induced netrin-1/DCC/VEGF signaling might be involved in PAS pathogenesis through the enhancement of trophoblastic angiogenesis.

Test-treat-track-test-treat (5T) approach for Schistosoma haematobium elimination on Pemba Island, Tanzania.

BACKGROUND: After decades of praziquantel mass drug administration (MDA), several countries approach schistosomiasis elimination. Continuing MDA in largely uninfected populations no longer seems justified. Alternative interventions to maintain the gains or accelerate interruption of transmission are needed. We report results, strengths, and shortcomings of novel test-treat-track-test-treat (5T) interventions in low Schistosoma haematobium prevalence areas on Pemba, Tanzania. METHODS: School- and household-based surveys were conducted in 2021 and 2022 to monitor the S. haematobium and microhematuria prevalence and assess the impact of interventions. In 2021, 5T interventions were implemented in 15 low-prevalence areas and included: (i) testing schoolchildren in primary and Islamic schools for microhematuria as a proxy for S. haematobium, (ii) treating positive children, (iii) tracking them to their households and to water bodies they frequented, (iv) testing individuals at households and water bodies, and (v) treating positive individuals. Additionally, test-and-treat interventions were implemented in the 22 health facilities of the study area. RESULTS: The S. haematobium prevalence in the school-based survey in 15 low-prevalence implementation units was 0.5% (7/1560) in 2021 and 0.4% (6/1645) in 2022. In the household-based survey, 0.5% (14/2975) and 0.7% (19/2920) of participants were infected with S. haematobium in 2021 and 2022, respectively. The microhematuria prevalence, excluding trace results, in the school-based survey was 1.4% (21/1560) in 2021 and 1.5% (24/1645) in 2022. In the household-based survey, it was 3.3% (98/2975) in 2021 and 5.4% (159/2920) in 2022. During the 5T interventions, the microhaematuria prevalence was 3.8% (140/3700) and 5.8% (34/594) in children in primary and Islamic schools, respectively, 17.1% (44/258) in household members, and 16.7% (10/60) in people at water bodies. In health facilities, 19.8% (70/354) of patients tested microhematuria-positive. CONCLUSIONS: The targeted 5T interventions maintained the very low S. haematobium prevalence and proved straightforward and feasible to identify and treat many of the few S. haematobium-infected individuals. Future research will show whether 5T interventions can maintain gains in the longer-term and expedite elimination. TRIAL REGISTRATION: ISRCTN, ISCRCTN91431493. Registered 11 February 2020, https://www.isrctn.com/ISRCTN91431493 .

The diagnostic utility of heparin-binding protein among patients with bacterial infections: a systematic review and meta-analysis.

BACKGROUND: Bacterial infections are considered a leading cause of hospitalization and death globally. There is still a need for a rapid and feasible biomarker for bacterial infections. Heparin-binding protein (HBP) was shown to be related to bacterial infections. The objective of the study is to investigate the diagnostic accuracy of HBP in bacterial infections. METHODS: Articles were screened in PubMed, SCOPUS, Web of Science, and Cochrane to recognize eligible studies. We included studies investigating the diagnostic accuracy of HBP and reported the necessary data to construct 2 × 2 tables. A univariate analysis was conducted to determine the pooled sensitivity and specificity, and a bivariate diagnostic random-effects model was used to calculate the optimal cut-off point. RESULTS: The analysis comprised sixteen studies in total. Plasma HBP showed a sensitivity of 0.90 (95% CI: [0.79, 0.96]) and a specificity of 0.87 (95% CI: [0.66, 0.96]) in diagnosing bacterial infections using blood samples. Pooling data from seven studies revealed that HBP in cerebrospinal fluid (CSF) has sensitivity and specificity of 96% (95% CI: [0.85, 0.99]), and 95% (95% CI: [0.89, 0.97]), respectively, for the diagnosis of bacterial meningitis. In urinary tract infections (UTI), urine-HBP was revealed to have a high diagnostic value in discriminating bacterial from non-bacterial UTI infection at a cut-off value of 32.868 ng/ml with sensitivity and specificity of 87%. CONCLUSION: HBP has shown a high diagnostic accuracy of bacterial infections, including UTI and meningitis. Further studies are needed to determine its prognostic value and whether it could guide antibiotic therapy.

Transcriptional analysis of oxidative and nitrosative stress on oral opportunistic Candida albicans.

The yeast Candida albicans is one of the most aggressive opportunistic pathogens in immunocompromised patients. The ability of the yeast to withstand stresses and radicals is of great concern. In the present study, four isolates of C. albicans were taken from patients with oral candidiasis and grown on RPMI for 24 hours at 37°C. Then, they were exposed to various concentrations of oxidative (H2O2) and nitrosative (HNO3) stress for two hours, and gene expression rates were measured through RT-PCR. After initial biofilm formation steps and growth validation, RNA extracted from the yeast and gene expression status were evaluated. Upon treatment with H2O2, the gene expression profile for ALS1, MLH1, and EXO1 showed approximately a fold increase in expression. While within HNO3 the yeast gene expression exhibited a dramatic increase in ALS1 up to 217 folds, while others such as MLH1, HWP1, and ERG11 showed a one-fold increase in the expression rate. The findings of this research indicate a considerable expression activity within the biofilm of Candida albicans, increased rate of DNA mismatch repair and break fixation may indicate the ability of the yeast to tolerate high concentrations of free radicals. It paves the way toward understanding the pathogenicity of the yeast and its survival capability inside macrophages. The study also revealed that the biofilm strategy of the yeast is more active within these stresses.

Therapeutic potentials of mesenchymal stem cells in the treatment of inflammatory bowel disease in rats.

Interleukin-1beta (IL-1ß) and interleukin-17A (IL-17A) have strong pro-inflammatory activities that are involved in inflammatory bowel diseases (IBDs). Mesenchymal stem cell (MSC) therapy is considered a promising treatment for IBD. This study was performed to understand the role of rat Nlrp3 inflammasome, Hmgb1, and pro-inflammatory cytokines (IL-1ß and IL-17a) in the pathogenesis of IBD. Also, to evaluate the role of human umbilical cord blood-MSCs (hUCB-MSCs) in the management of IBD. The rats were in four groups: normal controls, indomethacin-induced IBD group, indomethacin-induced IBD rats that received phosphate-buffered saline (PBS), and the IBD group that received hUCB-MSCs as a treatment. The messenger RNA (mRNA) expression levels of rat Nlrp3, Hmgb1, IL-1ß, and IL-17a were evaluated by quantitative real-time polymerase chain reaction. Histopathological examination of the small intestinal tissues of the studied rats was performed. There was a significant upregulation of the rat Nlrp3, IL-1ß, IL-17a mRNA expression (p < 0.001 for the three parameters), and Hmgb1 (p < 0.05) in the untreated IBD group compared to the normal control group. In the MSC-treated group, IL-1ß, IL-17a, and rat Nlrp3 mRNA expression significantly decreased compared to both the untreated IBD group and PBS group (p < 0.05 for all). hUCB-MSCs ameliorated IBD in rats by downregulating the pro-inflammatory cytokines (IL-1ß and IL-17a) and other inflammatory mediators such as Hmgb1 and rat Nlrp3.

Atypical chemokine receptor 4 (ACKR4/CCX-CKR): A comprehensive exploration across physiological and pathological landscapes in contemporary research.

Atypical chemokine receptor 4 (ACKR4), also known as CCX-CKR, is a member of the chemokine receptor family that lacks typical G protein signaling activity. Instead, ACKR4 functions as a scavenger receptor that can bind and internalize a wide range of chemokines, influencing their availability and activity in the body. ACKR4 is involved in various physiological processes, such as immune cell trafficking and the development of thymus, spleen, and lymph nodes. Moreover, ACKR4 has been implicated in several pathological conditions, including cancer, heart and lung diseases. In cancer, ACKR4 plays a complex role, acting as a tumor suppressor or promoter depending on the type of cancer and the stage of the disease. For instance, ACKR4 may inhibit the growth and metastasis of breast cancer, but it may also promote the progression of hepatocellular carcinoma and gastric cancer. In inflammatory situations, ACKR4 has been found to modulate the recruitment and activation of immune cells, contributing to the pathogenesis of diseases such as myocardial infraction and pulmonary sarcoidosis. The study of ACKR4 is still ongoing, and further research is needed to fully understand its role in different physiological and pathological contexts. Nonetheless, ACKR4 represents a promising target for the development of novel therapeutic strategies for various diseases.

The exo-microRNA (miRNA) signaling pathways in pathogenesis and treatment of stroke diseases: Emphasize on mesenchymal stem cells (MSCs).

A major factor in long-term impairment is stroke. Patients with persistent stroke and severe functional disabilities have few therapy choices. Long noncoding RNAs (lncRNAs) may contribute to the regulation of the pathophysiologic processes of ischemic stroke as shown by altered expression of lncRNAs and microRNA (miRNAs) in blood samples of acute ischemic stroke patients. On the other hand, multipotent mesenchymal stem cells (MSCs) increase neurogenesis, and angiogenesis, dampen neuroinflammation, and boost brain plasticity to improve functional recovery in experimental stroke models. MSCs can be procured from various sources such as the bone marrow, adipose tissue, and peripheral blood. Under the proper circumstances, MSCs can differentiate into a variety of mature cells, including neurons, astrocytes, and oligodendrocytes. Accordingly, the capability of MSCs to exert neuroprotection and also neurogenesis has recently attracted more attention. Nowadays, lncRNAs and miRNAs derived from MSCs have opened new avenues to alleviate stroke symptoms. Accordingly, in this review article, we examined various studies concerning the lncRNAs and miRNAs' role in stroke pathogenesis and delivered an overview of the therapeutic role of MSC-derived miRNAs and lncRNAs in stroke conditions.