Risk factors for vancomycin-associated acute kidney injury: A systematic review and meta-analysis.

AIMS: This systematic literature review and meta-analysis aimed to evaluate the risk factors for vancomycin-associated acute kidney injury (AKI) incidence. METHODS: This study assessed risk factors for vancomycin-associated AKI in adult patients by searching studies from PubMed, the Cochrane Library and Embase. Random effect models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Fifty-three studies were included in our meta-analysis. For patient factors, black race (OR 1.47, 95% CI: 1.16-1.87), Caucasian (OR 0.72, 95% CI: 0.58-0.90) and obesity (OR 1.46, 95% CI: 1.12-1.90) were associated with an increase in vancomycin-associated AKIs. In terms of vancomycin-related factors, longer treatment duration (>14 d; OR 1.73, 95% CI: 1.06-2.83), serum vancomycin trough level >15 µg/mL (OR 2.10, 95% CI: 1.43-3.07) and vancomycin trough level >20 µg/mL (OR 2.84, 95% CI: 1.48-5.44) increased the risks of vancomycin-associated AKI. For comorbidities and clinical factors, renal disease (OR 2.19, 95% CI: 1.51-3.17) showed the highest odds of vancomycin-associated AKI, followed by hepatic disease, intensive care unit admission, heart failure, sepsis, coronary heart disease and diabetes mellitus. For concomitant nephrotoxic drugs, amphotericin B (OR 5.21, 95% CI: 3.44-7.87) showed the highest odds of vancomycin-associated AKI, followed by acyclovir (OR 3.22, 95% CI: 1.39-7.46), vasopressors, loop diuretics, piperacillin-tazobactam and aminoglycoside. The use of any concomitant nephrotoxic agent (OR 1.74, 95% CI: 1.17-2.58) increased the odds of vancomycin-associated AKI. CONCLUSION: Our results may help predict the risk of vancomycin-associated AKI in the clinical setting.

Machine learning-based prediction of risk factors for abnormal glycemic control in diabetic cancer patients receiving nutrition support: a case-control study.

PURPOSE: To date, risk factors affecting abnormal glycemic control have not been investigated. This study aimed to analyze risk factors for hypoglycemia or hyperglycemia in diabetic cancer patients receiving nutritional support by using machine learning methods. METHODS: This retrospective two-center study was performed using medical records. Odds ratios and adjusted odds ratios were estimated from univariate and multivariate analyses, respectively. Machine learning algorithms, including five-fold cross-validated multivariate logistic regression, elastic net, and random forest, were developed to predict risk factors for hypoglycemia and hyperglycemia. RESULTS: Data from 127 patients were analyzed. The use of sulfonylurea (SU) and blood urea nitrogen (BUN) level > 20 mg/dL increased hypoglycemia by 6.3-fold (95% CI 1.30-30.47) and 5.0-fold (95% CI 1.06-23.46), respectively. In contrast, patients who received an actual energy intake/total energy expenditure (TEE) ≥ 120% and used dipeptidyl peptidase-4 (DPP-4) inhibitors had a higher risk of hyperglycemia by 19.3- (95% CI 1.46-254.78) and 3.3-fold (95% CI 1.23-8.61), respectively. An initial blood glucose level ≥ 182.5 mg/dL also increased the risk of hyperglycemia by 15.3-fold. AUROC values for all machine learning methods indicated acceptable and excellent performance for hypoglycemia and hyperglycemia. CONCLUSION: The use of SU and BUN level > 20 mg/dL increased the risk of hypoglycemia, whereas an initial blood glucose level ≥ 182.5 mg/dL, a supplied actual energy intake/ TEE ≥ 120%, and the use of DPP-4 inhibitors increased the risk of hyperglycemia.

Risk Scoring System for Vancomycin-Associated Acute Kidney Injury.

Vancomycin-associated acute kidney injury (AKI) remains a major challenge for patients and clinicians. This study aimed to construct a risk scoring system for vancomycin-associated AKI. We retrospectively reviewed medical records of patients who underwent therapeutic drug monitoring for vancomycin from June 2018 to July 2019. We selected possible risk factors for AKI by univariate and multivariable logistic regression analyses and developed a scoring system for vancomycin-associated AKI. Machine learning methods were utilized to predict risk factors for the occurrence of AKI. The incidence of vancomycin-associated AKI was 31.7% among 104 patients included in this study. A bodyweight ≤60 kg (two points), a Charlson comorbidity index ≥3 (two points), a vancomycin trough serum level >15 µg/ml (one point), and concomitant use of ≥6 nephrotoxic agents (two points) were included to construct a risk scoring system based on the coefficient from the logistic regression model. The area under the receiver operating characteristic curve (AUROC) (mean, 95% confidence interval (CI)) across 10 random iterations using five-fold cross-validated multivariate logistic regression, elastic net, random forest, support vector machine (SVM)-linear kernel, and SVM-radial kernel models was 0.735 (0.638-0.833), 0.737 (0.638-0.835), 0.721 (0.610-0.833), 0.739 (0.648-0.829), and 0.733 (0.640-0.826), respectively. For total scores of 0-1, 2-3, 4-5, 6-7, the risk of vancomycin-associated AKI was 5, 25, 45, and 65%, respectively. Our scoring system can be applied to clinical settings in which several nephrotoxic agents are used along with vancomycin therapy.

Menopause is an inflection point of age-related immune changes in women.

Elevated proinflammatory cytokines in postmenopausal women is considered as one of the causes increasing the incidence of chronic inflammatory diseases. However, the details of postmenopausal immune changes have not yet been fully revealed. Thus, we investigated age-related immune changes in women and compared immune responses in postmenopausal and reproductive-age women. A total of 34 postmenopausal women and 91 reproductive-age women were included in the study. After isolating peripheral blood mononuclear cells, analysis of immunophenotypes and intracellular cytokine profiles were done. The proportion of natural killer (NK) cells was significantly higher, and the ratio of TNF-α- to IL-10-producing CD3+CD4 + T cells (Th1 to Th2) and the ratio of Th17 cells to CD4+CD25+Foxp3+ regulatory T (Treg) cells (Th17 to Treg) were higher, in postmenopausal women than in reproductive-age women. The Treg cell proportion was negatively correlated with the Th1 and Th2 cell proportions in reproductive-age women but not in postmenopausal women. As age increased, the proportion of Tregs was increased in reproductive-age women (r = 0.302, p = 0.004), whereas the proportion of Th1 cells was increased in postmenopausal women (r = 0.466, p = 0.005). FSH levels showed a positive correlation with Fopx3+ T cell and Treg cell (p = 0.04, 0.053, respectively), whereas Th17/Treg ratio and Th1 cell showed negative correlation with FSH.(p = 0.045, 0.024, respectively). In conclusion, postmenopausal women have higher proinflammatory immune statuses, as demonstrated by increased proportions of NK, Th1, and Th17 cells, altered correlations among NK and T cell subsets, and compromised balances between effector T cell subsets.

Risk Scoring System of Mortality and Prediction Model of Hospital Stay for Critically Ill Patients Receiving Parenteral Nutrition.

Predicting the clinical progression of intensive care unit (ICU) patients is crucial for survival and prognosis. Therefore, this retrospective study aimed to develop the risk scoring system of mortality and the prediction model of ICU length of stay (LOS) among patients admitted to the ICU. Data from ICU patients aged at least 18 years who received parenteral nutrition support for ≥50% of the daily calorie requirement from February 2014 to January 2018 were collected. In-hospital mortality and log-transformed LOS were analyzed by logistic regression and linear regression, respectively. For calculating risk scores, each coefficient was obtained based on regression model. Of 445 patients, 97 patients died in the ICU; the observed mortality rate was 21.8%. Using logistic regression analysis, APACHE II score (15-29: 1 point, 30 or higher: 2 points), qSOFA score ≥ 2 (2 points), serum albumin level < 3.4 g/dL (1 point), and infectious or respiratory disease (1 point) were incorporated into risk scoring system for mortality; patients with 0, 1, 2-4, and 5-6 points had approximately 10%, 20%, 40%, and 65% risk of death. For LOS, linear regression analysis showed the following prediction equation: log(LOS) = 0.01 × (APACHE II) + 0.04 × (total bilirubin) - 0.09 × (admission diagnosis of gastrointestinal disease or injury, poisoning, or other external cause) + 0.970. Our study provides the mortality risk score and LOS prediction equation. It could help clinicians to identify those at risk and optimize ICU management.

Intravenous Immunoglobulin G Improves Pregnancy Outcome in Women with Recurrent Pregnancy Losses with Cellular Immune Abnormalities.

PROBLEM: We investigated the therapeutic effect of intravenous immunoglobulin (IVIG) in women with recurrent pregnancy loss (RPL). METHOD OF STUDY: This was a retrospective observational study. Total 189 RPL women who experienced ≥2 miscarriages were enrolled and investigated conventional etiologies, thrombophilia, and cellular immunity. Patients were divided into four groups; known etiology with (Gr1) and without cellular immune abnormality (Gr2), unknown etiology with (Gr3) and without cellular immune abnormality (Gr4). IVIG was administrated from early pregnancy to 30 weeks of gestation to women with cellular immune abnormality (Gr1 + Gr3). RESULTS: Cellular immune abnormalities (increased level or cytotoxicity of NK cells and Th1/Th2 ratio) were present in 111 of 189 RPL women (58.7%). Live birth rates of women with and without cellular immune abnormality were not different (Gr1 + Gr3, 84.8% versus Gr2 + Gr4, 89.7%). Furthermore, IVIG success rates were the same between Gr1 and Gr3, those who had cellular immune abnormality. Nevertheless lack of an appropriate control in this study, our IVIG outcome demonstrated better live birth rate compared with those of other investigators. CONCLUSION: Treatment modalities stratified by underlying etiologies of RPL may improve pregnancy outcome. Administration of IVIG is likely to have clinical efficacy in RPL women with cellular immune abnormality.

Enhanced expression of neuronal nitric oxide synthase and phospholipase C-gamma1 in regenerating murine neuronal cells by pulsed electromagnetic field.

Pulsed electromagnetic field (PEMF) has been shown to improve the rate of peripheral nerve regeneration. In the present study we investigated the expression of neuronal nitric oxide synthase (nNOS) and phospholipase C-gamma1 (PLC-gamma1) in regenerating rat laryngeal nerves during the exposure to PEMF after surgical transection and reanastomosis. Axons were found to regenerate into the distal stump nearly twice faster in PEMF-exposed animals than in the control. Consistently, motor function was better recovered in PEMF-treated rats. The expression of nNOS and PLC-gamma1 was highly enhanced in the regenerated nerves.

Intravenous immunoglobulin G modulates peripheral blood Th17 and Foxp3(+) regulatory T cells in pregnant women with recurrent pregnancy loss.

PROBLEM: Th17 cells and Foxp3(+) regulatory T (Treg) cells have been proposed as new risk factors for recurrent pregnancy loss (RPL). Intravenous immunoglobulin G (IVIG) was reported to modulate various immune cells. In this study, we investigated the effect of IVIG on the levels of Th17 and Treg cells and pregnancy outcome in women with RPL. METHOD OF STUDY: Thirty-seven pregnant women with RPL were enrolled in this study. All had cellular immune abnormality in preconceptional evaluation. Blood was drawn on the day of IVIG treatment and 1 week later from the study subjects during early pregnancy. The proportions of IL-17(+) and Foxp3(+) T cells were analyzed using flow cytometry. RESULTS: Study population was divided into four groups (Q1-Q4) based on ascending order of the levels of Th17 and Foxp3(+) T cells. IVIG down-regulated Th17 cells in the highest quartile, Q4 (P = 0.001), and up-regulated CD4(+)  Foxp3(+) T cells in Q1 and Q2 (P = 0.025 and 0.029, respectively). In addition, Th17/CD4(+)  Foxp3(+) T cell ratio decreased in Q4 (P = 0.040). We also found a positive trend between successful pregnancy outcome and CD8(+)  IL-17(+) T cells before IVIG treatment (P = 0.05). CONCLUSION: Intravenous immunoglobulin G treatment modulated imbalance of Th17 and Foxp3(+) Treg cells in pregnant RPL women with cellular immune abnormality.

Determination of clinical cellular immune markers in women with recurrent pregnancy loss.

PROBLEM: Dysregulated natural killer (NK) immunity and T-cell immunity are associated with recurrent pregnancy loss (RPL). We aim to define clinically relevant NK and T-cell parameters for RPL and determine their cutoff values. METHODS OF STUDY: Ninety-five women with RPL (>3) including 42 idiopathic and 53 known-etiology RPL, and 29 age-matched fertile controls were enrolled. Peripheral blood immunophenotype, NK cell cytotoxicity (NKC), and T-helper (Th) 1 and Th2 cytokine producing cell ratios (Th1/Th2) were measured using flowcytometry. The cutoff values were determined using Youden's J with likelihood ratio (LR) >2. RESULTS: Natural killer cell percentage and NKC, TNF-α(+) Th1 cells, and TNF-α/IL-10 producing Th1/Th2 cell ratio were significantly higher in idiopathic RPL than controls. By the area under the curve (AUC) analysis, NK cell percentage (AUC = 0.691), NKC (AUC = 0.649), TNF-α(+) Th1 cells (AUC = 0.681) and Th1/Th2 cell ratio (AUC = 0.660) were highly specific for RPL. The cutoff values for NK cell percentage, NKC (E:T cell ratio 25:1), and TNF-α/IL-10 producing Th1/Th2 cell ratio are 16.1, 23.8, and 36.2%, respectively. Seventy-six percent of idiopathic RPL showed at least one of more immune abnormalities by these criteria. CONCLUSION: Differences in NK cell percentages, NKC and Th1/Th2 cell ratio differentiated RPL from fertile controls.

Th17 and regulatory T cells in women with recurrent pregnancy loss.

The immune system of pregnant women is tightly controlled to defend against microbial infections and at the same time, to accept an embryo or the fetus, which are expressing semi-allogenic paternal antigens. Furthermore, inflammation-like processes are crucial for tissue growth, remodeling, and differentiation of the decidua during pregnancy. Dysregulation of elaborate immune control may lead reproductive failure, such as implantation failure, recurrent pregnancy loss (RPL), preterm birth, intrauterine fetal growth restriction, and preeclampsia. Until recent years, a balance between Th1 and Th2 cells was believed to be the key immune regulatory mechanism of T-cell immunology especially during pregnancy. Since the identification of regulatory T cells was made, the mechanism of immune regulation has become a major issue in immunologic research. Also, the recent identification of Th17 cells has drawn our attention to a new immune effector. The balance between Th17 and regulatory T cells may explain more about the pathophysiology of reproductive failure. This review will discuss relevant human literature on regulatory T and Th17 cells in normal reproductive physiology and in women with RPL and infertility.

Foxp3(high) and Foxp3(low) Treg cells differentially correlate with T helper 1 and natural killer cells in peripheral blood.

Regulatory T (Treg) cells interact with B, natural killer (NK), and dendritic cells in addition to other T cells. In this study, we aimed at determining whether Foxp3(+) T cells and subpopulations have any correlation with other lymphocyte subsets and their functions in a systemic immune environment. Peripheral blood was drawn from 22 nonpregnant healthy women. T, B, and NK cell subpopulations were measured by immunophenotype analysis. Intracellular Foxp3, cytokine expression (tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], and interleukin-10 [IL]-10), and NK-cell cytotoxicity were analyzed by flow cytometric analysis. Correlations between Foxp3(+) T cells and other immune variables were analyzed under control of age and menstrual phases. Foxp3(+), Foxp3(low), and CD4(+)Foxp3(+) cells significantly correlated with CD4(+)CD25(+), CD4(+)CD25(dim), and CD4(+)CD25(bright) cells. Foxp3(+), Foxp3(low), and CD4(+)Foxp3(+) cells positively correlated with CD3(+) and CD3(+)CD4(+) T cells, but negatively correlated with CD3(-)CD56(+) and CD3(-)CD56(dim) NK cells. CD4(+)Foxp3(high) Treg cells were positively correlated with CD3(+)CD4(+)TNF-α(+) (p = 0.014) and negatively correlated with CD3(+)CD8(+)IL-10(+) T cells (p = 0.001). The ratio of type 1/2 cytokine-producing CD3(+)CD8(+) cells demonstrated a positive correlation with CD4(+)Foxp3(high) cells (p ≤ 0.01). CD8(+)Foxp3(+) cells were positively correlated with CD3(+)CD4(+)IL-10(+) cells (p = 0.007) and negatively correlated with CD3(+)CD8(+)TNF-α(+) cells (p = 0.008). In conclusion, each Foxp3(+) Treg cell subpopulation has unique immune interaction, which controls particular subsets of lymphocytes.