Machine Learning Predicts the Fall Risk of Total Hip Arthroplasty Patients Based on Wearable Sensor Instrumented Performance Tests

BackgroundThe prevalence of falls affects the wellbeing of aging adults and places an economic burden on the healthcare system. Integration of wearable sensors into existing fall risk assessment tools enables objective data collection that describes the functional ability of patients. In this study, supervised machine learning was applied to sensor-derived metrics to predict the fall risk of patients following total hip arthroplasty.MethodsAt preoperative, 2-week, and 6-week postoperative appointments, patients (n = 72) were instrumented with sensors while they performed the timed-up-and-go walking test. Preoperative and 2-week postoperative data were used to form the feature sets and 6-week total times were used as labels. Support vector machine and linear discriminant analysis classifier models were developed and tested on various combinations of feature sets and feature reduction schemes. Using a 10-fold leave-some-subjects-out testing scheme, the accuracy, sensitivity, specificity, and area under the receiver-operator curve (AUC) were evaluated for all models.ResultsA high performance model (accuracy = 0.87, sensitivity = 0.97, specificity = 0.46, AUC = 0.82) was obtained with a support vector machine classifier using sensor-derived metrics from only the preoperative appointment. An overall improved performance (accuracy = 0.90, sensitivity = 0.93, specificity = 0.59, AUC = 0.88) was achieved with a linear discriminant analysis classifier when 2-week postoperative data were added to the preoperative data.ConclusionThe high accuracy of the fall risk prediction models is valuable for patients, clinicians, and the healthcare system. High-risk patients can implement preventative measures and low-risk patients can be directed to enhanced recovery care programs.     

The 2018 International Consensus Meeting Minor Criteria for Chronic Hip and Knee Periprosthetic Joint Infection: Validation From a Single Center

BackgroundRecently, a revised definition of the minor criteria scoring system for diagnosing periprosthetic joint infection (PJI) was developed by the second International Consensus Meeting on musculoskeletal infection. The new system combines preoperative and intraoperative findings, reportedly achieving high sensitivity and specificity. We aimed to validate the modified scoring system at a high-volume center.MethodsWe retrospectively reviewed patients who underwent a revision total hip or knee arthroplasty at our institution from May 2015 to August 2018. Serum C-reactive protein, synovial white blood cell count and polymorphonuclear percentage, leukocyte esterase test, alpha-defensin, microbiological and histologic results, and documented existence of sinus tract and intraoperative purulence were available for all patients. Cases with at least 1 major criterion were considered as infected. Using the new minor criteria, a score of ≥6 reflects PJI, while a score <3 can be considered as noninfected. Sensitivity, specificity, mean accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) were analyzed.ResultsA total of 345 cases were included. A cutoff score of ≥6 points had the following diagnostic performance: area under the curve (AUC) = 0.90; ACC = 0.88; sensitivity = 0.96; specificity = 0.84; PPV = 0.70; NPV = 0.98. Diagnostic performance was better for the hip (AUC = 0.92; ACC = 0.90; sensitivity = 0.96; specificity = 0.86; PPV = 0.81; NPV = 0.98) than the knee (AUC = 0.89; ACC = 0.85; sensitivity = 0.95; specificity = 0.83; PPV = 0.59; NPV = 0.98).ConclusionThe modified scoring system proposed by the 2018 International Consensus Meeting in diagnosing PJI showed high sensitivity and a good performance, especially as rule-out diagnostic criteria. The cutoff level seems to be different between the hip and knee. Further validation studies considering the acknowledged limitations are recommended.     

Osteoporosis quality indicators using healthcare utilization data

Summary  

Healthcare utilization data may be used to examine the quality of osteoporosis management by identifying dual-energy X-ray absorptiometry (DXA) testing (sensitivity = 98%, specificity = 93%) and osteoporosis pharmacotherapy (κ = 0.81) with minimal measurement error.     

The Efficacy of the ImmuKnow Assay for Evaluating the Immune Status in Human Immunodeficiency Virus and Hepatitis C Virus–Coinfected Patients

Background

The survival of human immunodeficiency virus (HIV)-infected patients has significantly improved since the introduction of antiretroviral therapy (ART). However, the mortality due to hepatitis C virus (HCV)-related liver disease has not been reduced in HIV/HCV-coinfected patients, and HCV has recently become the most significant cause of death in HIV/HCV-coinfected patients. Liver transplantation might be one of the treatments of choice in such cases, but it is very difficult to evaluate the immune status of these patients due to ART, anti-HCV treatment, and HIV-related immunocompromised state.

Aim

The aim of this study was to evaluate the immune status in HIV/HCV-coinfected patients using the Cylex ImmuKnow assay, which was designed to monitor the global immune status by measuring the adenosine triphosphate (ATP) levels produced by activated CD4+ T cells.

Methods

Twenty-eight HIV/HCV-coinfected patients were included in this study. We evaluated their immune activity using the ImmuKnow assay, and compared the data with those of HCV mono-infected patients indicated for liver transplantation as well as healthy controls.

Results

The ATP levels of HIV/HCV-coinfected patients were significantly higher than those of HCV mono-infected liver transplant recipients (P < .001), and were significantly lower than those of healthy controls (P = .001).

Conclusion

The ImmuKnow assay was considered to be a useful tool to evaluate the immune status of HIV/HCV-coinfected patients.     

Immune functional assay for immunosuppressive management in post‐transplant malignancy

Uemura T, Riley TR, Khan A, Hollenbeak C, Schreibman I, Ghahramani N, Reeves B, Domen RE, Zander DS, Kadry Z. Immune functional assay for immunosuppressive management in post‐transplant malignancy.
Clin Transplant 2011: 25: E32–E37. © 2010 John Wiley & Sons A/S. Abstract: Immunosuppression management in post‐transplant malignancy is challenging because of a lack of objective immunologic assessment tools. The ImmuKnow assay measures the ATP level from CD4 T cells, quantifying cell‐mediated immunity and providing an insight into the immune status of transplant recipients. Its potential use in patients with post‐transplant de novo malignancy was evaluated. Thirteen adult transplant patients with de novo malignancy were divided into survivors (n = 9) and non‐survivors (n = 4) after malignancy treatment. Tacrolimus and the ImmuKnow levels were monitored before, during, and after malignancy treatment. The ImmuKnow level in non‐survivors group was significantly lower before and after malignancy treatment compared to survivors group (p = 0.013 and 0.0014 respectively). In survivor group, the ImmuKnow level was significantly decreased during malignancy treatment (p = 0.019) but recovered to the initial level after the treatment. However, in non‐survivor group, the ImmuKnow level remained suppressed throughout the observed period despite a reduction in immunosuppressive drug levels. The ImmuKnow assay can be an objective means evaluating immune status of patients with de novo malignancy. The ImmuKnow assay can express the degree of immune suppression induced by chemotherapeutic or radiation therapy and may be a useful tool in optimizing the timing of re‐introduction of immunosuppression after malignancy treatment.     

Circulating mitochondrial genes detect acute cardiac allograft rejection: Role of the mitochondrial calcium uniporter complex

Acute rejection after heart transplantation increases the risk of chronic dysfunction. Disturbances in mitochondrial function may play a contributory role, however, the relationship between histological signs of rejection in the human transplanted heart and expression levels of circulating mitochondrial genes, such as the mitochondrial Ca²⁺ uniporter (MCU) complex, remains unexplored. We conducted an RNA-sequencing analysis to identify altered mitochondrial genes in serum and to evaluate their diagnostic accuracy for rejection episodes. We included 40 consecutive samples from transplant recipients undergoing routine endomyocardial biopsies. In total, 112 mitochondrial genes were identified in the serum of posttransplant patients, of which 28 were differentially expressed in patients with acute rejection (p < .05). Considering the receiver operating characteristic analysis with an area under the curve (AUC) >0.900 to discriminate patients with moderate or severe degrees of rejection, we found that the MCU system showed a strong capability for detection: MCU (AUC = 0.944, p < .0001), MCU/MCUR1 ratio (AUC = 0.972, p < .0001), MCU/MCUB ratio (AUC = 0.970, p < .0001), and MCU/MICU1 ratio (AUC = 0.970, p < .0001). Mitochondrial alterations are reflected in peripheral blood and are capable of discriminating between patients with allograft rejection and those not experiencing rejection with excellent accuracy. The dysregulation of the MCU complex was found to be the most relevant finding.     

Blood CD9+ B cell,a biomarker of bronchiolitis obliterans syndrome after lung transplantation

Bronchiolitis obliterans syndrome is the main limitation for long‐term survival after lung transplantation. Some specific B cell populations are associated with long‐term graft acceptance. We aimed to monitor the B cell profile during early development of bronchiolitis obliterans syndrome after lung transplantation. The B cell longitudinal profile was analyzed in peripheral blood mononuclear cells from patients with bronchiolitis obliterans syndrome and patients who remained stable over 3 years of follow‐up. CD24^hiCD38^hi transitional B cells were increased in stable patients only, and reached a peak 24 months after transplantation, whereas they remained unchanged in patients who developed a bronchiolitis obliterans syndrome. These CD24^hiCD38^hi transitional B cells specifically secrete IL‐10 and express CD9. Thus, patients with a total CD9⁺ B cell frequency below 6.6% displayed significantly higher incidence of bronchiolitis obliterans syndrome (AUC = 0.836, PPV = 0.75, NPV = 1). These data are the first to associate IL‐10‐secreting CD24^hiCD38^hi transitional B cells expressing CD9 with better allograft outcome in lung transplant recipients. CD9‐expressing B cells appear as a contributor to a favorable environment essential for the maintenance of long‐term stable graft function and as a new predictive biomarker of bronchiolitis obliterans syndrome–free survival.     

Clinical utility of CD4 + function assessment (ViraCor-IBT ImmuKnow test) in lung recipients

The ImmuKnow assay measures cell-mediated immunity, quantifying ATP production from peripheral blood CD4 + T-cells in solid-organ transplant patients who undergo immunosuppressive therapy. We aimed to measure functional immunity in lung transplant recipients and correlate Immuknow values with immunosuppression levels, presence of chronic lung allograft dysfunction (CLAD) and infections. We evaluated 61 lung recipients who underwent follow-up for lung transplantation between 2010 and 2014. Rejection and infection were retrospectively analyzed. The association between over-immunosuppression and a number of predictors was assessed by means of univariate and multivariate logistic regression models. 71 out of 127 samples (56%) showed an over-immunosuppression with an ImmuKnow assay mean level of 112.92 ng/ml (SD ± 58.2), vs. 406.14 ng/ml (SD ± 167.7) of the rest of our cohort. In the over-immunosuppression group we found 51 episodes of infection (71%) (OR 2.754, 95% CI 1.40–5.39; P-value 0.003). In the other group, only 25 samples (44%) were taken during an infectious episode. The mean absolute ATP level was significantly different between patients with or without infection (202.38 ± 139.06 ng/ml vs. 315.51 ± 221.60 ng/ml; P < 0.001). RAS (Restrictive allograft syndrome) was associated to low ImmuKnow level (P < 0.001). These results were confirmed by the multivariate analysis. The ImmuKnow assay levels were significantly lower in infected lung transplant recipients compared with non-infected recipients and in RAS patients.     

Diffusion tensor imaging as an adjunct tool for the diagnosis of varicocele

A noninvasive imaging technique providing information about testicular dysfunction in testes with varicocele would be useful. The aim is to measure the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in testes of infertile men with varicocele and to assess interobserver agreement. Sixteen infertile men with varicocele and 14 age‐matched controls underwent 1.5 T diffusion tensor imaging (DTI) MRI. Testicular ADC and FA were measured by two radiologists independently. Parametric and nonparametric statistical tests were applied to compare between the ADC and FA of testes with varicocele and normal testes. Interobserver agreement was evaluated. The interobserver variability for ADC (0.915) and FA (0.948) was very good. No differences in ADC (p = 0.294) were found between the two groups. FA was significantly lower in testes with varicocele compared to age‐matched controls (p < 0.001). An optimal cut‐off of FA 0.08 was found for the diagnosis of varicocele (sensitivity = 88%, specificity = 93.5%, positive predictive value = 91.6% and negative predictive value = 90.6%). Based on our results, FA is useful for the diagnosis of testes in infertile men with varicocele, with very good interobserver agreement. Therefore, DTI may be used as a noninvasive imaging tool in the work‐up of varicocele.     

Detection and Functional Analysis of Tumor Infiltrating T-Lymphocytes (TIL) in Liver Metastases from Colorectal Cancer

Background  Tumor-infiltrating T lymphocytes (TIL) play an important role in primary colorectal cancer, but their activity in liver metastases has not yet been investigated. The aim of this study was to examine whether tumor-selective infiltration, activation, and cytotoxic activity of TIL can be demonstrated in situ in colorectal liver metastases. Methods  TIL were obtained from liver metastases and corresponding normal liver tissue of 16 patients with colorectal liver metastases. Characterization of TIL in situ was performed by multicolor flowcytometric analysis. Presence of tumor antigen-reactive T cells was evaluated by interferon gamma Elispot analysis. Results  TIL in colorectal liver metastases responding against tumor antigens were present in most patients. Although the proportions of CD3⁺ T cells were comparable in liver metastasis and normal liver tissue, metastases contained significantly enhanced proportions of CD4⁺ cells (49% vs. 22%, P < .001). Among all CD4⁺ T helper cells, the proportion of activated (CD4⁺CD25⁺) effector cells was significantly increased in liver metastases (15.0% vs. 7.8%, P = .003). Metastases showed significantly higher proportions of activated (CD69⁺ [70.1% vs. 49.8%, P = .02] and CD25⁺ [4.1% vs. .6%, P = .06]) and cytotoxically active (CD107a⁺) CD8⁺ TIL (3.2% vs. 1.3%, P = .03). Importantly, the presence of activated T helper cells correlated with the frequencies of cytotoxic T lymphocytes that exerted cytotoxic activity in situ (P = .02). Conclusion  CD4⁺ and CD8⁺ TIL are selectively activated in liver metastases, and cytotoxic T lymphocytes exert tumor-selective cytotoxic activity in situ in the presence of activated T helper cells, suggesting the requirement of in-situ-activated T helper cells for efficient cytotoxic T lymphocytes effector function. P. Wagner and M. Koch contributed equally to this study. An erratum to this article can be found at     

Co‐localized immune protection using dexamethasone‐eluting micelles in a murine islet allograft model

The broad application of ß cell transplantation for type 1 diabetes is hindered by the requisite of lifelong systemic immunosuppression. This study examines the utility of localized islet graft drug delivery to subvert the inflammatory and adaptive immune responses. Herein, we have developed and characterized dexamethasone (Dex) eluting Food and Drug Administration‐approved micro‐Poly(lactic‐co‐glycolic acid) micelles and examined their efficacy in a fully major histocompatibility complex‐mismatch murine islet allograft model. A clinically relevant dose of 46.6 ± 2.8 μg Dex per graft was confirmed when 2 mg of micelles was implemented. Dex‐micelles + CTLA‐4‐Ig (n = 10) resulted in prolonged allograft function with 80% of the recipients demonstrating insulin independence for 60 days posttransplant compared to 40% in empty micelles + CTLA‐4‐Ig recipients (n = 10, P = .06). Recipients of this combination therapy (n = 8) demonstrated superior glucose tolerance profiles, compared to empty micelles + CTLA‐4‐Ig recipients (n = 4, P < .05), and significantly reduced localized intragraft proinflammatory cytokine expression. Histologically, increased insulin positive and FOXP3⁺ T cells were observed in Dex‐micelles + CTLA‐4‐Ig grafts compared to empty micelles + CTLA‐4‐Ig grafts (P < .01 and P < .05, respectively). Localized drug delivery via micelles elution has the potential to alter the inflammatory environment, enhances allograft survival, and may be an important adjuvant approach to improve clinical islet transplantation outcomes.     

Effect of Mammalian Target of Rapamycin Inhibition on Activated Regulatory T-Cell Expansion in Kidney Transplantation

BackgroundThe mammalian target of rapamycin (mTOR) plays a critical role in the host immune response in organ transplantation. This study evaluates the regulatory benefits of mTOR inhibitors in kidney transplant recipients (KTRs).MethodsThe mTOR-dependent immune-regulating effects in KTRs were evaluated by examining T-cell subsets among peripheral blood mononuclear cells from 79 KTRs. Recipients included an early introduction of everolimus (EVR) and reduced-exposure tacrolimus group (n = 46) and a standard tacrolimus-based without EVR (non-EVR) group (n = 33).ResultsTrough concentrations of tacrolimus at 3 months and 1 year were significantly lower in the EVR group than the non-EVR group (both P < .001). In addition, the respective proportions of patients without estimated glomerular filtration rate < 20% in the EVR and non-EVR groups were 100% and 93.3% at 1 year, 96.3% and 89.7% at 2 years, and 96.3% and 89.7% at 3 years after blood collection, respectively (P = .079). The frequencies of CD3⁺ T cells and CD4⁺ T cells among peripheral blood mononuclear cells were comparable between groups. Total CD25^highCD127⁻CD4⁺ regulatory T (Treg) cells were similar in the EVR and non-EVR groups. In contrast, circulating CD45RA⁻CD25^highCD127⁻CD4⁺ activated Treg cells were significantly higher in the EVR group (P= .008).ConclusionThese results suggest that the early introduction of mTOR benefits long-term kidney graft function and circulating activated Treg-cell expansion in KTRs.     

Measurement of CD4+ T‐cell function in predicting allograft rejection and recurrent hepatitis C after liver transplantation

Hashimoto K, Miller C, Hirose K, Diago T, Aucejo F, Quintini C, Eghtesad B, Corey R, Yerian L, Lopez R, Zein N, Fung J. Measurement of CD4+ T‐cell function in predicting allograft rejection and recurrent hepatitis C after liver transplantation.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01169.x
© 2009 John Wiley & Sons A/S. Abstract: Recurrence of hepatitis C virus (HCV) can be difficult to distinguish from acute cellular rejection (ACR) following liver transplantation. The Cylex Immune Function Assay (ImmuKnow) provides objective measure of recipient’s immune function. The goal is to assess the ability of this assay to distinguish these similar conditions. A retrospective review was performed in 54 recipients with HCV. ImmuKnow assays were measured with allograft biopsies. Levels of adenosine triphosphate (ATP) release from CD4+ T cells (ng/mL) were compared with the following biopsy result classifications: 365 ± 130 with ACR (n = 11), 152 ± 100 with recurrent HCV (n = 26), 240 ± 71 with normal biopsies (n = 12), and 157 ± 130 with overlapping features of ACR and recurrent HCV (n = 5). Recipients with recurrent HCV had lower immune response than those with ACR (p < 0.0001).Using a cutoff level of 220, the sensitivity and specificity for distinguishing two conditions were 88.5% and 90.9%, respectively. When recipients with overlapping features had low immune response, three of four recipients’ subsequent biopsies showed recurrent HCV. In conclusion, the ImmuKnow assay can be a sensitive and specific additional test for distinguishing recurrent HCV from ACR and may be useful for predicting which recipients may be most vulnerable to recurrent HCV.     

Natural killer cell function predicts severe infection in kidney transplant recipients

The aim of this study was to determine if natural killer cell number (CD3^?/CD16^±/CD56^±) and cytotoxic killing function predicts severity and frequency of infection in kidney transplant recipients. A cohort of 168 kidney transplant recipients with stable graft function underwent assessment of natural killer cell number and functional killing capacity immediately prior to entry into this prospective study. Participants were followed for 2 years for development of severe infection, defined as hospitalization for infection. Area under receiver operating characteristic (AUROC) curves were used to evaluate the accuracy of natural killer cell number and function for predicting severe infection. Adjusted odds ratios were determined by logistic regression. Fifty‐nine kidney transplant recipients (35%) developed severe infection and 7 (4%) died. Natural killer cell function was a better predictor of severe infection than natural killer cell number: AUROC 0.84 and 0.75, respectively (P = .018). Logistic regression demonstrated that after adjustment for age, transplant function, transplant duration, mycophenolate use, and increasing natural killer function (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74‐0.90; P < .0001) but not natural killer number (OR 0.96, 95% CI 0.93‐1.00; P = .051) remained significantly associated with a reduced likelihood of severe infection. Natural killer cell function predicts severe infection in kidney transplant recipients.     

Early interstitial macrophage infiltration with mild dysfunction is associated with subsequent kidney graft loss

Macrophage infiltration is associated with unfavorable kidney graft outcome in protocol biopsies, but few studies have evaluated its impact on clinical practice. We therefore prospectively evaluated 37 kidney transplant recipients (KTRs) who underwent kidney biopsy due to slight increases in serum creatinine, or mild proteinuria (>0.3 g/24 hr), in the first post‐transplant year. Banff score, CD68⁺ count (score 0‐3) by immunohistochemistry, and 1‐year DSA were assessed. DGF was reported in 10 (27%) patients, 6 (16%) had normal biopsy, 7 (19%) borderline lesions, 13 (35%) IFTA, and 11 (30%) other lesions. Fifteen KTRs had grade 3 CD68⁺ infiltration, and 47% developed de novo DSA. During a 6.2 ± 2.7 year follow‐up, four patients (11%) suffered from biopsy‐proven T‐cell rejection, 17 KTRs (46%) lost their graft (12 in the grade 3 CD68⁺ group). Graft survival was lower in KTRs with grade 3 CD68⁺ infiltration (P = 0.0074; log‐rank test). Grade 3 CD68⁺ infiltrate was an independent predictor of graft loss (HR 5.41, 95% CI 1.74‐16.8; P = 0.003), together with more severe graft dysfunction at biopsy (HR 6.41, 95% CI 2.57‐16; P < 0.001). We conclude that grade 3 CD68⁺ interstitial infiltration is associated with increased risk of subsequent graft loss independent of other factors.     

High proportion of CD95+ and CD38+ in cultured CD8+ T cells predicts acute rejection and infection,respectively, in kidney recipients

The aim of this study was to find noninvasive T-cell markers able to predict rejection or infection risk after kidney transplantation.We prospectively examined T-lymphocyte subsets after cell culture stimulation (according to CD38, CD69, CD95, CD40L, and CD25 expression) in 79 first graft recipients from four centers, before and after transplantation. Patients were followed up for one year.Patients who rejected within month-1 (n = 10) showed high pre-transplantation and week-1 post-transplantation percentages of CD95⁺, in CD4⁺ and CD8⁺ T-cells (P < 0.001 for all comparisons). These biomarkers conferred independent risk for early rejection (HR:5.05, P = 0.061 and HR:75.31, P = 0.004; respectively). The cut-off values were able to accurately discriminate between rejectors and non-rejectors and Kaplan–Meier curves showed significantly different free-of-rejection time rates (P < 0.005). Patients who rejected after the month-1 (n = 4) had a higher percentage of post-transplantation CD69⁺ in CD8⁺ T-cells than non-rejectors (P = 0.002). Finally, patients with infection (n = 41) previously showed higher percentage of CD38⁺ in CD8⁺ T-cells at all post-transplantation times evaluated, being this increase more marked in viral infections. A cut-off of 59% CD38⁺ in CD8⁺ T-cells at week-1, week-2 and month-2 reached 100% sensitivity for the detection of subsequent viral infections.In conclusion, predictive biomarkers of rejection and infection risk after transplantation were detected that could be useful for the personalized care of kidney recipients.     

Hydroxychloroquine and maintenance immunosuppression use in kidney transplant recipients: Analysis of linked US registry and claims data

Hydroxychloroquine (HCQ) is an antimalarial drug with immunomodulatory effects used to treat systemic lupus erythematosus (SLE) and scleroderma. The antiviral effects of HCQ have raised attention in the context of the COVID-19 pandemic, although safety is controversial. We examined linkages of national transplant registry data with pharmaceutical claims and Medicare billing claims to study HCQ use among Medicare-insured kidney transplant recipients with SLE or scleroderma (2008–2017; N = 1820). We compared three groups based on immunosuppression regimen 7 months-to-1 year post transplant: (a) tacrolimus (Tac) + mycophenolic acid (MPA) + prednisone (Pred) (referent group, 77.7%); (b) Tac + MPA + Pred + HCQ (16.5%); or (c) other immunosuppression + HCQ (5.7%). Compared to the referent group, recipients treated with other immunosuppression + HCQ had a 2-fold increased risk of abnormal ECG or QT prolongation (18.9% vs. 10.7%; aHR,_1.121.96_3.42, p = .02) and ventricular arrhythmias (15.2% vs. 11.4%; aHR,_1.001.81_3.29, p = .05) in the >1-to-3 years post-transplant. Tac + MPA + Pred + HCQ was associated with increased risk of ventricular arrhythmias (13.5% vs. 11.4%; aHR,_1.021.54_2.31, p = .04) and pancytopenia (35.9% vs. 31.4%; aHR,_1.031.31_1.68, p = .03) compared to triple immunosuppression without HCQ. However, HCQ-containing regimens were not associated with an increased risk of death or graft failure. HCQ may be used safely in selected kidney transplant recipients in addition to their maintenance immunosuppression, although attention to arrhythmias is warranted.     

Fasting parameters for estimation of stimulated β cell function in islet transplant recipients with or without basal insulin treatment

In order to assess β cell secretory capacity after islet transplantation, standardized mixed meal stimulation tests are often used. But these tests are cumbersome and the effect of exogenous insulin on the test results is unclear. The aim of our study was to determine to what extent fasting glycemic indices can estimate stimulated β cell function in islet transplant recipients with and without basal insulin. In total 100 mixed meal stimulation tests, including 31 with concurrent basal insulin treatment, were performed in 36 islet transplant recipients. In a multivariate model, fasting C-peptide and fasting glucose together estimated peak C-peptide with R² = .87 and area under the curve (AUC) C-peptide with a R² = .93. There was a larger increase of glucose during tests in which exogenous insulin was used (+7.9 vs +5.3 mmol/L, P < .001) and exogenous insulin use was associated with a slightly lower estimated peak C-peptide (relative change: −15%, P = .02). In islet transplant recipients the combination of fasting C-peptide and glucose can be used to accurately estimate stimulated β cell function after a mixed meal stimulation test, whether exogenous basal insulin is present or not. These data indicate that graft function can be reliably determined during exogenous insulin treatment and that regular islet graft stimulation tests can be minimized.     

Attenuation of the Systemic Inflammatory Response and Infectious Complications After Gastrectomy with Preoperative Oral Arginine and ω-3 Fatty Acids Supplemented Immunonutrition

Background  Past trials have shown perioperative immunonutrition to improve the outcome for patients with gastric cancer. The present study was designed to evaluate the effect of preoperative oral immunonutrition on cellular immunity, the duration of the systemic inflammatory response syndrome (SIRS), and detailed postoperative complications in patients with gastric cancer. Methods  Sixty patients with gastric cancer were randomly assigned to two groups: one group received immune-enhanced formulas supplemented with arginine and ω-3 fatty acids (immune-enhancing diet (ID) group, n = 30); the other received standard formulas (conventional diet (CD) group, n = 30) for 7 days before the operation. These groups were well matched in terms of age, sex, operations, cancer stages, and intraoperative variables. The postoperative outcome was evaluated based on clinical variables, including postoperative infectious complications, noninfectious complications, and SIRS duration. In addition, the perioperative state of cellular immunity was evaluated and compared between the two groups. Results  The incidence of postoperative infectious complications in the ID group (6%) was significantly (p < 0.05) lower than that of the CD group (28%). The duration of SIRS in the ID group (0.77 ± 0.9 days) was significantly (p < 0.05) shorter than that in the CD group (1.34 ± 1.45 days). The postoperative lymphocyte and CD4⁺T-cell counts significantly decreased (p < 0.05) in both groups. However, the number of CD4⁺T-cells on preoperative day 1 and postoperative day 7 was significantly (p < 0.05) higher in the ID group than in the CD group. Conclusions  Preoperative oral immune-enhanced formulas supplemented with arginine and ω-3 fatty acids enhanced the immune status of the patients, reduced the duration of SIRS, and decreased the incidence of postoperative infectious complications. CD4⁺T-cell immunity likely played an important role in the modulation of the postoperative immune and inflammatory response after gastrectomy.     

Immune responses following tocilizumab therapy to desensitize HLA-sensitized kidney transplant candidates

Kidney transplant candidates (KTCs) who are HLA highly sensitized (calculated panel-reactive alloantibodies >95%) have poor access to deceased kidney transplantation. In this single-center prospective study, 13 highly sensitized desensitization-naïve KTCs received IV tocilizumab (8 mg/kg) every 4 weeks. We evaluated tolerability as well as immune responses, that is, T cell, B cell, T follicular helper (Tfh) subsets, blood cytokines (IL-6, soluble IL-6 receptor-sIL-6R-, IL-21), blood chemokines (CXCL10, CXCL13), and anti-HLA alloantibodies. Tocilizumab treatment was well-tolerated except in one patient who presented spondylodiscitis, raising a note of caution. Regarding immune parameters, there were no significant changes of percentages of lymphocyte subsets, that is, CD3⁺, CD3⁺/CD4⁺, CD3⁺/CD8⁺ T cells, and NK cells. This was also the case for Tfh cell subsets, B cells, mature B cells, plasma cells, pre-germinal center (GC) B cells, and post-GC B cells, whereas we observed a significant increase in naïve B cells (p = .02) and a significant decrease in plasmablasts (p = .046) over the tocilizumab treatment course. CXCL10, CXCL13, IL-21, total IgG, IgA, and IgM levels did not significantly change during tocilizumab therapy; conversely, there was a significant increase in IL-6 levels (p = .03) and a huge increase in sIL-6R (p = .00004). There was a marginal effect on anti-HLA alloantibodies (class I and class II). To conclude in highly sensitized KTCs, tocilizumab as a monotherapy limited B cell maturation; however, it had almost no effect on anti-HLA alloantibodies.