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To highlight the progress and future direction of stem-cell based regenerative therapies for the treatment of corneal disease.Corneal stem cell-based therapies, such as limbal stem cell transplantation, corneal stromal stem cell transplantation, endothelial stem cell transplantation, and stem cell-derived extracellular vesicles have demonstrated promising results in the laboratory. Although most are still in preclinical development or early phase clinical trials, these stem cell-based therapies hold potential to facilitate tissue regeneration, restore native function, and inhibit pathologic disease processes such as fibrosis, inflammation, and neovascularization.Stem cell-based therapy offers a promising therapeutic option that can circumvent several of the challenges and limitations of traditional surgical treatment. This concise review summarizes the progress in stem-cell based therapies for corneal diseases along with their history, underlying mechanisms, limitations, and future areas for development.

Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations.Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital.Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model's prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/ .Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers' practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.

The purpose of this study was to report a case of corneal transparency for 7 months after the formation and persistence of a Descemet fluid cleft.We report the case of a 64-year-old woman undergoing anterior chamber reformation 2 months after Baerveldt implantation of the right eye. During the procedure, the ophthalmic viscoelastic was inadvertently injected into the posterior stroma, nearly isolating the corneal endothelial cell layer, and creating a Descemet fluid cleft filled with viscoelastic. The patient was managed conservatively and monitored near monthly for corneal decompensation.The cornea remained centrally clear for 207 days after the initial anterior chamber reformation until the collapse of the viscoelastic cleft. When the cleft completely collapsed, the cornea became diffusely edematous, and the patient underwent cataract removal and intraocular lens placement without need for Descemet stripping endothelial keratoplasty to maintain vision. During these 7 months, the patient's best-corrected visual acuity remained stable at 20/25 +2 or better. Intraocular pressure was also stable, averaging 18.2 mm Hg.We hypothesize that corneal transparency can be maintained in the absence of endothelial cell function provided that aqueous humor cannot reach the cornea and disrupt the arrangement of the interfibrillar space.

Background: eNOS (endothelial nitric oxide synthase) is an endothelial cell (EC)–specific gene predominantly expressed in medium- to large-sized arteries where ECs experience atheroprotective laminar flow with high shear stress. Disturbed flow with lower average shear stress decreases eNOS transcription, which leads to the development of atherosclerosis, especially at bifurcations and curvatures of arteries. This prototypic arterial EC gene contains 2 distinct flow-responsive cis-DNA elements in the promoter, the shear stress response element (SSRE) and the KLF (Krüppel-like factor) element. Previous in vitro studies suggested their positive regulatory functions on flow-induced transcription of EC genes including eNOS. However, the in vivo function of these cis-DNA elements remains unknown. Methods: Insertional transgenic mice with a mutation at each flow-responsive cis-DNA element were generated using a murine eNOS promoter–β-galactosidase reporter by linker-scanning mutagenesis and compared with episomal-based mutations in vitro. DNA methylation at the eNOS proximal promoter in mouse ECs was assessed by bisulfite sequencing or pyrosequencing. Results: Wild type mice with a functional eNOS promoter–reporter transgene exhibited reduced endothelial reporter expression in the atheroprone regions of disturbed flow (n=5). It is surprising that the SSRE mutation abrogated reporter expression in ECs and was associated with aberrant hypermethylation at the eNOS proximal promoter (n=7). Reporter gene silencing was independent of transgene copy number and integration position, indicating that the SSRE is a critical cis-element necessary for eNOS transcription in vivo. The KLF mutation demonstrated an integration site–specific decrease in eNOS transcription, again with marked promoter methylation (n=8), suggesting that the SSRE alone is not sufficient for eNOS transcription in vivo. In wild type mice, the native eNOS promoter was significantly hypermethylated in ECs from the atheroprone regions where eNOS expression was markedly repressed by chronic disturbed flow, demonstrating that eNOS expression is regulated by flow-dependent DNA methylation that is region-specific in the arterial endothelium in vivo. Conclusions: We report, for the first time, that the SSRE and KLF elements are critical flow sensors necessary for a transcriptionally permissive, hypomethylated eNOS promoter in ECs under chronic shear stress in vivo. Moreover, eNOS expression is regulated by flow-dependent epigenetic mechanisms, which offers novel mechanistic insight on eNOS gene regulation in atherogenesis.

Background Combined liver-kidney transplantation (CLKT) improves survival for liver transplant recipients with renal dysfunction; however, the tenuous perioperative hemodynamic and metabolic milieu in high-acuity CLKT recipients increases delayed graft function and kidney allograft failure. We sought to analyze whether delayed KT through pumping would improve kidney outcomes following CLKT. Methods A retrospective analysis (University of California Los Angeles [n = 145], Houston Methodist Hospital [n = 79]) was performed in all adults receiving CLKT at 2 high-volume transplant centers from February 2004 to January 2017, and recipients were analyzed for patient and allograft survival as well as renal outcomes following CLKT. Results A total of 63 patients (28.1%) underwent delayed implantation of pumped kidneys during CLKT (dCLKT) and 161 patients (71.9%) received early implantation of nonpumped kidneys during CLKT (eCLKT). Most recipients were high-acuity with median biologic model of end-stage liver disease (MELD) score of, 35 for dCLKT and 34 for eCLKT (P = ns). Pretransplant, dCLKT had longer intensive care unit stay, were more often intubated, and had greater vasopressor use. Despite this, dCLKT exhibited improved 1-, 3-, and 5-year patient and kidney survival (P = 0.02) and decreased length of stay (P = 0.001), kidney allograft failure (P = 0.012), and dialysis duration (P = 0.031). This reduced kidney allograft futility (death or continued need for hemodialysis within 3 mo posttransplant) for dCLKT (6.3%) compared with eCLKT (19.9%) (P = 0.013). Conclusions Delayed implantation of pumped kidneys is associated with improved patient and renal allograft survival and decreased hospital length of stay despite longer kidney cold ischemia. These data should inform the ethical debate as to the futility of performing CLKT in high-acuity recipients.

We hope that at the point that readers see this CJASN article, they will have already read the three accompanying CJASN articles on patient preference information and patient-centered innovation in KRT ([1][1][⇓][2]–[3][3]). These four articles represent a combined effort to chronicle the

The principal aim of this review is to highlight recent advances in our understanding of cognitive dysfunction in major depressive disorder (MDD). We review new assessment and treatment approaches, in which cognition and associated psychosocial dysfunction are considered primary outcomes.Current work suggests that cognitive dysfunction reduces occupational productivity, and interferes broadly with domains of day-to-day and social functioning. These findings imply that cognitive dysfunction interacts with emotional and social factors relevant to MDD. Recent advances in screening instruments enable standardized detection of cognitive symptoms in MDD. Clinical trials suggest that cognitive symptoms are suitable targets and primary outcomes of psychological and pharmacological treatments.A growing interest in cognitive dysfunction in MDD has improved our ability to assess and treat MDD. Future research will be strengthened by the use of consistent terminology, standardized cognitive screening, and treatments that target cognitive dysfunction in MDD. Integration of emotional and social treatment strategies may further advance clinical efficacy.

Background. Data about vaccine efficacy in solid organ transplant patients are limited. We previously reported our initial observation of a 6.2% immunogenicity rate in kidney transplant recipients (KTRs) after administration of 1 dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine. We sought to report our observations of anti-SARS-CoV-2 antibody in KTRs after 2 doses of the SARS-CoV-2 mRNA vaccine. Methods. We identified 105 KTRs who received 2 doses of the Pfizer-BioNTech or Moderna mRNA-1273 vaccine per availability and had anti-SARS-CoV-2 labs obtained at least 2 wk following administration of the second dose. Antibody testing was performed using 3 clinically validated qualitative and semiquantitative assays. Results. KTRs had a 36.2% antibody response rate, whereas an age ≥68 years and a longer time from transplant were factors associated with antibody response. Conclusions. The low antibody response in KTRs may be associated with the immunosuppressive state. More data are needed to evaluate if KTRs may require higher vaccine doses or an additional booster dose to increase their ability to mount an immune response to the SARS-CoV-2 vaccine.

PURPOSE OF REVIEW BK virus is a significant risk factor for kidney allograft dysfunction and loss among renal transplant recipients. Currently, there is no proven effective treatment except for the reduction of immunosuppression. In this review, we discuss diagnostic challenges and current treatment options for BK in kidney transplant recipients. RECENT FINDINGS Antiviral and antibiotic therapies have been employed for BK viraemia with variable efficacy. In addition, novel therapeutic regimens such as adoptive transfer of targeted T cells have been described as possible treatment options for recipients with BK nephropathy. BK can also be seen in the native kidneys of pancreas, heart, lung and liver transplant recipients, suggesting that BK screening measures should be employed to other solid organ transplant recipients. SUMMARY Early screening for BK combined with reduction of immunosuppression remains the mainstay of treatment for BK viraemia. New therapeutic advances demonstrate promise in vitro; however, the in-vivo efficacy will be demonstrated by future studies.

A 64-year-old man who presented with photopsia was found to have elevated intraocular pressure in one eye and optic disc swelling in the other eye. He was initially diagnosed with neurocysticercosis and later metastatic lung adenocarcinoma. The purpose of this paper is to report a rare case of bilateral glare as the first sign of diffusely metastatic cancer and to raise clinical suspicion for systemic malignancy in the presence of multiple ocular manifestations.

Lifestyle interventions must be effective at engaging participants beyond the initial intervention period in order to be successful in reducing long-term cardiovascular risks. Unfortunately, there is a lack of evidence for improvement in long-term cardiovascular outcomes following participation in lifestyle interventions. Participant engagement has been shown to wane after the first 12 months of participation. This gradual reduction in engagement may be responsible for the limited evidence for an effect on long-term cardiovascular risk. The objective of this study is to assess patient, program and community characteristics associated with better participant engagement after 2 years in a weight management program. This is an observational study of 330,522 participants enrolled in MOVE! programs within the Veterans Healthcare Administration (VHA) from 2008 to 2013. The MOVE! program is a nationwide weight management intervention integrated into primary care within the VHA and provided free to Veterans. Participant engagement is defined as the number of MOVE! program visits per year for each participant. Engagement is assessed at 6 months, 12 months, and 24 months following the first program visit. Bivariate statistics and multivariate generalized linear models were used to assess factors associated with patient engagement at each time point. At the first MOVE! visit, the average participant age was 56.3 years old (SD=12.0) with a body mass index of 36.9 [Standard Deviation (SD)=5.4). Most participants were male (87.9 and lived in an urban area (69.7%) an average of 38.6 miles from the MOVE! program (SD=48.5). Eight percent (7.5%) of participants had a Charlson Comorbidity Index of 4 or more at the time of their first visit. Engagement decreased as time from the first visit increased. Patients had a median of 4.0 visits per year at 6 months [Interquartile Range (IQR)=2.0-8.0], 2.0 visits per year at 12 months (IQR=1.0-5.0), and 1.0 visit per year at 24 months (IQR=0.5-3.0). In adjusted models of 24-month engagement, older age (beta=0.03, p

The aim of this study was to compare endothelial cell loss and graft success 6 months after endothelial keratoplasty (EK) with paired donor corneas stored in Optisol GS and Life4°C solutions and their associated storage chambers.Donor pairs were stored, one in Optisol GS and the other in Life4°C, and prepared for Descemet stripping automated EK or Descemet membrane EK. Matched pairs of recipients with Fuchs dystrophy were randomized to 1 member of each donor pair. Clarity of recipient stroma, intraocular pressure, and complications were followed for 6 months. Central endothelial images of the donor cornea at screening and 3 and 6 months after EK were analyzed by a masked central reading center. Dual grading of endothelial cell density was performed using the center method. Differences in endothelial cell density and cell loss were examined by paired analysis.Thirty-two pairs were enrolled, and 27 were analyzed (5 had improper matching or loss to follow-up). Donor age was 59 ± 14 years, median death-to-surgery time was 4 days (range, 2-9 days), 6 recipient pairs had Descemet membrane EK, and 21 had Descemet stripping automated EK. Recipient age was comparable in the Optisol GS and Life4°C groups (70 vs. 68 years, respectively, P = 0.46). Six-month central endothelial cell loss did not differ significantly between the Life4°C and Optisol GS groups (18 ± 18% vs. 20 ± 20%, respectively, P = 0.55). All recipient corneas were clear at 6 months in both groups.Endothelial cell loss and graft success were comparable at 6 months for paired donor corneas stored in Optisol GS and Life4°C.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01657500.

Objective:Estimate association between postpartum antiretroviral adherence and breast milk HIV-1 transmission.Design:Prospective cohort study.Methods:Mother–infant pairs were randomized after delivery to immediately begin receiving 28 weeks of either triple maternal antiretrovirals (zidovudine, lami

This study aimed to assess kidney dysfunction in general surgical patients and examine the effect on postoperative mortality and morbidity.An estimated 13% of the US population has chronic kidney disease (CKD), but awareness among patients and caregivers is lacking.The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) data sets for 2005-2007 were analyzed. Preoperative kidney function was assessed by the Modification of Diet in Renal Disease formula for estimated glomerular filtration rate (eGFR) and staged according to National Kidney Foundation. Cross-sectional analyses were performed for 30-day mortality (Cox proportional hazard) and incidence of major complications (nominal logistic regression). A case-control cohort of colectomy cases was analyzed comparing patients in the stage 4 CKD group and the no CKD group (no-CKD).Sixty-four percent of evaluable patients had reduced eGFR, but eGFR was not evaluable in 28% of the surgical cases. In the 260,352 evaluable cases, adjusted hazard ratio for 30-day mortality was 2.30 [95% confidence interval (CI), 2.11-2.51] for stage 3 CKD; 3.37 (95% CI, 3.01-3.76) for stage 4 CKD; and 3.05 (95% CI, 2.68-3.47) for stage 5 CKD compared with no-CKD (P0.0001). CKD was an independent risk factor for having major complications postsurgery [stage 3, odds ratio (OR) = 1.24 (95% CI, 1.19-1.29); stage 4, OR = 1.65 (95% CI, 1.52-1.78); and stage 5 CKD, OR = 1.40 (95% CI, 1.30-1.51); P0.0001]. The case-control for colectomy was confirmatory: increased 30-day mortality in stage 4 CKD versus no-CKD (hazard ratio = 2.58, 95% CI, 1.13-5.92; P = 0.025).Renal insufficiency may be underrecognized in the general and vascular (noncardiac) surgery population, is a leading independent predictor of poor early postoperative outcomes, and should be routinely assessed in the preoperative setting.

BACKGROUND This study reviewed the outcomes of a screening protocol for BK viremia to determine if early diagnosis, followed by immunosuppression minimization, would prevent progression to nephropathy and graft loss. METHODS This review included 369 renal transplant recipients tested for BK virus at serial time points after transplantation. Management included immunosuppression minimization plus cidofovir treatment for BK nephropathy. RESULTS Recipients received tacrolimus-based immunosuppression, with 8% prednisone-free and 6% who received desensitization. With a mean follow-up of 22 ± 10 months, 16% (n = 57) of recipients became BK viremia positive. The median (range) time to diagnosis was 3 (1-17) months. Because renal biopsy was performed selectively, 59% of recipients underwent biopsy, with 47% showing BK nephropathy. Seventy-four percent of recipients cleared the virus at a median (range) time of 9 (3-33) months, with four grafts lost to BK nephropathy. Cidofovir-treated recipients displayed a higher viral load at diagnosis but showed equivalent renal function at last evaluation. In multivariate analysis, recipient age, Asian ethnicity, deceased donor, and prednisone use were factors independently associated with BK viremia. Actuarial survival of BK-positive grafts was worse than that of BK-negative grafts (P

Speed and acceleration are essential for field sport athletes. However, the mechanical factors important for field sport acceleration have not been established in the scientific literature. The purpose of this study was to determine the biomechanical and performance factors that differentiate sprint acceleration ability in field sport athletes. Twenty men completed sprint tests for biomechanical analysis and tests of power, strength, and leg stiffness. The sprint intervals analyzed were 0-5, 5-10, and 0-10 m. The subjects were split into a faster and slower group based on 0- to 10-m velocity. A 1-way analysis of variance determined variables that significantly (p ≤ 0.05) distinguished between faster and slower acceleration. All subject data were then pooled for a correlation analysis to determine factors contributing most to acceleration. The results showed that 0- to 5-m (∼16% difference) and 0- to 10-m (∼11% difference) contact times for the faster group were significantly lower. Times to peak vertical and horizontal force during ground contact were lower for the faster group. This was associated with the reduced support times achieved by faster accelerators and their ability to generate force quickly. Ground contact force profiles during initial acceleration are useful discriminators of sprint performance in field sport athletes. For the strength and power measures, the faster group demonstrated a 14% greater countermovement jump and 48% greater reactive strength index. Significant correlations were found between velocity (0-5, 5-10, and 0-10 m) and most strength and power measures. The novel finding of this study is that training programs directed toward improving field sport sprint acceleration should aim to reduce contact time and improve ground force efficiency. It is important that even during the short sprints required for field sports, practitioners focus on good technique with short contact times.

Background and Purpose— Transient ischemic attack (TIA) patients are at risk of recurrent vascular events. The primary objectives were to evaluate among TIA patients the prevalence of sleep apnea and among patients with sleep apnea auto-titrating continuous positive airway pressure (auto-CPAP) adherence. The secondary objective was to describe among TIA patients with sleep apnea the recurrent vascular event rate by auto-CPAP use category. Methods— All intervention patients received auto-CPAP for 2 nights, but only intervention patients with evidence of sleep apnea received auto-CPAP for the remainder of the 90-day period. Intervention patients received polysomnography at 90 days after TIA. Control patients received polysomnography at baseline and at 90 days. Acceptable auto-CPAP adherence was defined as ≥4 hours per night for ≥75% of nights. Vascular events included recurrent TIA, stroke, hospitalization for congestive heart failure, myocardial infarction, or death. Results— We enrolled 70 acute TIA patients: 45 intervention and 25 control. The majority of patients had sleep apnea: 57% at baseline and 59% at 90 days. Among the 30 intervention patients with airflow obstruction, 12 (40%) had acceptable auto-CPAP adherence, 18 (60%) had some use, and none had no use. Three intervention patients (12%) had recurrent events compared with 1 (2%; P =0.13) control patient. The vascular event rate was highest among sleep apnea patients with no CPAP use: none, 16%; some, 5%; acceptable adherence 0% ( P =0.08). Conclusions— Sleep apnea is common among acute TIA patients. It appears feasible to provide auto-CPAP in the acute TIA period. Larger studies should evaluate whether a strategy of diagnosing and treating sleep apnea can reduce recurrent vascular events after TIA.

Many published articles have documented the impact of prostate-cancer treatment on sexual functioning in men treated for localized disease. Surprisingly, the literature on interventions to rehabilitate men’s sexual functioning is much more limited. In this article, we review the sexual-rehabilitation interventions for prostate-cancer patients and identify a number of common themes across interventions. We also identify areas where further research is needed and propose a conceptual model based on psychological and nursing theories and informed by the published research.

OBJECTIVE: To describe the choices and tradeoffs inherent in 3 published strategies that combine first- and second-trimester markers for Down syndrome screening. METHODS: Published marker distributions for Down syndrome and unaffected pregnancies in the first and second trimesters were combined with a maternal age distribution and age-associated Down syndrome risk in a statistical model to compare sequential, contingent, and integrated screening. RESULTS: Sequential and contingent screening strategies are always less efficient (higher false-positive rate for a given detection rate) than integrated screening, but the reduction in efficiency is dependent on the combination of risk cutoffs chosen. At a fixed false-positive rate, sequential and contingent strategies perform better when a higher proportion of the false positives occur in the second trimester. For all 3 strategies, increasing the overall false-positive rate from 2% to 5% increases detection (from approximately 85% to 91%). Although associated with reduced screening efficiency compared with integrated screening, both sequential and contingent screening identify the majority of detected Down syndrome cases early. With contingent screening, the process is also completed in the first trimester for most women. CONCLUSION: Integrated screening is the most efficient of the 3 strategies, but it is possible to select risk cutoffs for both sequential and contingent strategies that minimize losses in efficiency while maintaining early detection and early completion. For all of these strategies, well-designed intervention trials are needed to determine acceptability to women and providers in primary care settings and to assess real-world performance.

Background Malignancies, a well-known complication of immunosuppressive therapy in renal transplant recipients, represent an important cause of long-term morbidity and mortality. One approach to addressing this problem is identifying agents that display antineoplastic properties concomitant with their immunosuppressive effects. Methods We examined the neoplasms among 1008 renal transplant recipients treated at a single center with sirolimus-cyclosporine +/- prednisone. Results Clinical and laboratory data, including 62.3+/-26.1 months follow-up (range 27.1-131), revealed 36 tumors in 35 patients (3.6%) presenting at 32.5+/-29.8 months. The 2.4% incidence of skin tumors, the most common neoplasms, was 1.58-fold greater than the general U.S. population. In addition to a 0.4% incidence of posttransplant lymphoproliferative disorders (PTLD) and a 0.2% incidence of renal cell carcinomas, we observed single cases of breast, bladder, endometrial, lung, and brain neoplasms as well as leukemia. The mean trough drug concentrations at the time of diagnosis in affected recipients were within our putative target ranges. In addition to eleven graft losses due to death with a functioning kidney, two were related to chronic rejection following reduced immunosuppression, and one, therapeutic nephrectomy for PTLD. Five of twelve deaths were caused by malignancies; four others among 1008 patients over the entire follow-up were attributed to cardiovascular events; one, to respiratory failure; and two, at distant locations to unknown causes. Conclusions The sirolimus-cyclosporine +/- prednisone combination appears likely to be associated with a reduced incidence of tumors.

Rationale High and low blood pressure (BP) levels are common following acute stroke, with up to 60% of patients being hypertensive (SBP > 160 mmHg) and nearly 20% having relative hypotension (SBP < 140 mmHg), within the first few hours of ictus, both conditions being associated with an adverse prognosis. At present, the optimum management of blood pressure in the immediate post-stroke period is unclear.Objective The primary aim of the Controlling Hypertension and Hypotension Immediately Post-Stroke (CHHIPS) Pilot Trial is to assess whether hypertension and relative hypotension, manipulated therapeutically in the first 24 h following acute stroke, affects short-term outcome measures.Design The CHHIPS Pilot Trial is a UK based multi-centre, randomized, double-blind, placebo-controlled, titrated dose trial.Setting Acute stroke and medical units in teaching and district general hospitals, in the UK.Patients The CHHIPS Pilot Study aims to recruit 2050 patients, with clinically suspected stroke, confirmed by brain imaging, who have no compelling indication or contraindication for BP manipulation.Study outcomes The primary outcome measure will be the effects of acute pressor therapy (initiated

Background. We previously reported that the use of basiliximab together with sirolimus permits a window of recovery from delayed graft function before the introduction of reduced-dose cyclosporine. The present study reviews our experience with the substitution of thymoglobulin for basiliximab as induction therapy for recipients at increased risk for early acute rejection episodes. Methods. We retrospectively reviewed 145 cadaveric renal allograft recipients who received either basiliximab (n = 115) or thymoglobulin (n = 30) in combination with sirolimus and prednisone, followed by delayed introduction of reduced doses of cyclosporine. Recipients were stratified as high immune responders if they were African American, a retransplant recipient, or a recipient with a panel-reactive antibody greater than 50%. All other recipients were considered low immune responders. Results. Basiliximab-treated high immune responders exhibited a higher incidence of acute rejection episodes (26%) than either basiliximab-treated low immune responders (10%, P=0.04) or thymoglobulin-treated high immune responders (3%, P=0.01). The median time to initiation of cyclosporine was 12 days; cyclosporine was initiated when the serum creatinine level was 2.5 mg/dL or less. Patients with early return of renal function displayed a lower incidence of acute rejection episodes than those with later recovery of function (P=0.003). High immune responders treated with basiliximab expressed a higher mean serum creatinine level at 3 months (P

BACKGROUND We investigated a novel immunosuppressive protocol including thymoglobulin induction in combination with sirolimus and corticosteroids, followed by introduction of markedly reduced exposures to cyclosporine to prevent pancreas-transplant rejection. METHODS A 7-day course of thymoglobulin (1.5 mg/kg per day) was begun on postoperative day (POD) 0, together with 15 mg of sirolimus on POD 1, and followed by 5 mg per day, targeting these doses to achieve a trough of 10 to 20 ng/mL. When the serum creatinine was below 2.5 mg/dL, cyclosporine was introduced at 50 mg twice daily with dose adjustment to maintain a trough concentration of 100 to 125 ng/mL. RESULTS The 18 patients included 14 simultaneous pancreas-kidney and 4 pancreas-after-kidney transplant recipients. Two patients were African-American, three patients had a pretransplant panel reactive antibody greater than 20%, and the human leukocyte antigen (HLA) mismatch was 4.5+/-1 (mean+/-standard deviation). With a mean follow-up of 13.6+/-4.7 months, patient, kidney, and pancreas graft survivals are 100%, 100%, and 94%, respectively. A single pancreas graft was lost to thrombosis. There were no acute rejection episodes and no opportunistic infections. Mean hospital stay was 9+/-3 days. At 3 months posttransplantation, the mean value of serum creatinine was 1.2+/-0.3 mg/dL, fasting glucose was 88+/-15 mg/dL, and sirolimus dose at month 3 was 6.3+/-3 mg per day and at month 12 2.7+/-1 mg per day. The average total daily cyclosporine A dose at month 3 was 208+/-62 mg per day and 133+/-13 mg per day at 1 year. CONCLUSIONS This immunosuppressive regimen provided excellent prophylaxis against acute rejection with no opportunistic infections. We believe that careful monitoring of sirolimus and cyclosporine levels was critical to success of this protocol.

Background. Cytotoxic T-lymphocyte antigen 4 (CTLA4) has been shown to play a critical role in the down-regulation of the immune response. We retrospectively examined the association between acute rejection and two polymorphisms in the CTLA4 gene, the dinucleotide (AT) n repeat polymorphism in exon 3 and the single nucleotide polymorphism A/G at position 49 in exon 1, in a cohort of liver and kidney transplant recipients. Methods and Results. A total of 207 liver and 167 renal transplant recipients were analyzed. In the case of the (AT) n repeat polymorphism we found an increased incidence of acute rejection in association with allele 3 and 4 in both liver and kidney (P=0.002 and 0.05, respectively). In addition, in liver transplant recipients, allele 7 was associated with acute rejection independent of ethnicity (P

Background. We investigated whether recipients of living donor grafts who suffer an acute rejection progress to graft loss because of chronic rejection at a slower rate than recipients of cadaveric grafts. Methods. A retrospective review was made of 296 renal transplantations performed at Mount Sinai Hospital. Only grafts functioning for at least 3 months were included in this analysis. Demographic variables of donor and recipient age, race, sex, and serum creatinine at 3 months after transplantation were compared between groups. Results. Among the acute rejection-free cohort, the estimated 5-year graft survival was 90% for those receiving transplants from living relatives and 88% for those receiving cadaveric transplants (P=0.76). However, in grafts with early acute rejection, the 5-year survival was 40% for cadaveric recipients compared with 73% for living related graft recipients (P

Purpose: Identification of metastatic disease progression is often difficult but important. Previous studies of quality of life in metastatic disease have been limited by the small number of respondents who were not white or of lower socioeconomic status. Quality of life assessment is generally done using self-administration techniques but this method is of limited usefulness for patients of low socioeconomic status, many of whom have limited reading abilities. We evaluated the feasibility and validity of interviewer administration of 3 quality of life instruments for patients of low socioeconomic status with metastatic prostate cancer.Materials and Methods: We used instruments previously validated with self-administration methodology, including the European Organization for Research and Treatment of Cancer-Quality of Life Questionnaire-30, Functional Assessment of Cancer Therapy-General Scale and Quality of Life Index. Subjects were men with metastatic prostate cancer with stable (78) or progress...

Objective: To assess the effects of pregnancy on cyclosporine levels in six renal allograft patients. Methods: Maternal demographic, laboratory, clinical, and perinatal outcome data were recorded in six pregnant women with previous renal allografts receiving cyclosporine immunosuppression. The cyclosporine and serum creatinine levels were measured before pregnancy, during each trimester, and postpartum. Results: The mean (standard deviation [SD]) maternal age was 29.1 (3.8) years. Parity ranged from 0 to 3. Mean serum creatinine levels tended to be lower during pregnancy than before or after, as did the mean cyclosporine levels. After adjusting for dose, five of six patients had declines in cyclosporine level during pregnancy. The mean (SD) gestational age at delivery was 37.5 (2.8) weeks with a mean (SD) birth weight of 2837 (538) g. Conclusion: Pregnancy in patients with renal allografts can lead to a substantial decline in cyclosporine levels.

Background. The pathogenesis of chronic rejection likely involves an interplay between immunogenic and nonimmunogenic factors. The objective of this study was to determine the influence of cold ischemic preservation injury on the rate of progression to chronic rejection in the Lewis to F344 cardiac allograft model. Methods. To induce an ischemic injury, donor hearts were stored for 3 hr at 4°C in University of Wisconsin solution before transplantation. Allografts were excised at 1, 7, and 90 days after transplantation or at rejection. Vasculopathy was graded for degree of inti-mal thickening based on the involvement of vascular perimeter and luminal compromise. Results. The degree of vessel injury in ischemic injured allografts at 90 days was significantly greater than in nonischemic injured allografts (2.8±0.4 vs. 1.6±0.5, P

Mouse mAbs directed against the alpha/beta-TCR were tested in clinical phase II and in triple-blind, randomized phase III studies. A clinical phase II trial administered 50 mg of murine anti-human alpha/beta-TCR mAb (BMA 031) intravenously on the day of, as well as 2 and 4 days after, cadaveric donor renal transplantation in combination with a CsA/prednisone regimen. None of 12 patients showed even moderately adverse side effects. A phase III, triple-blind randomized trial enrolled 24 patients in the BMA 031 group and 22 patients in a placebo control group. BMA 031 treatment significantly reduced the incidence of rejection events within the first 10 posttransplant days to 1 patient versus 9 episodes in the placebo group (P < 0.01). By the end of 30 days, 6 rejection episodes had occurred in the BMA 031 group and 11 in the control cohort (P = NS). After a minimum of 30 months follow-up, the actual allograft survival rate was 87% in the BMA-treated group compared with 68% in the control cohort.

A mouse IgG1 mAb (R73) directed against the rat alpha/beta-TCR was documented not only to prolong the survival of allografts across major RT1 plus non-RT1 antigenic disparities, but also to display a synergistic immunosuppressive interaction with CsA. Heterotopic cardiac transplants from Buffalo (RT1b) rats survived significantly longer in Wistar-Furth (RT1u) hosts treated immediately after the operation with 0.25 mg/kg R73 i.v., with a mean survival time of 11.0 +/- 5.5 versus 6.8 +/- 1.2 days in the untreated group (P < 0.01). Administration of 0.5 or 5.0 mg/kg R73 displayed dose-dependent prolongation of survival to 17.0 +/- 8.3 days (P < 0.05) or 28.6 +/- 14.0 days (P < 0.01), respectively. One 0.5 mg/kg i.v. dose of R73 delivered to normal Wistar-Furth hosts produced peripheral T cell depletion that reversed after 16 days. Three injections of 0.5 mg/kg R73 on days 0, 2, and 4 prolonged allograft survival to 52.5 +/- 38.6 days compared with 17.0 +/- 8.3 days with a single dose (P < 0.01). Addition of 3 daily doses of 5 or 10 mg/kg CsA administered per oral gavage to a single dose of 0.05, 0.25, or 0.5 mg/kg R73 injected on day 0 produced a synergistic effect to prolong allograft survival, as determined by the rigorous median-effect analysis. The synergistic interaction, which may be explained by the inhibitory effect of CsA on Ca(2+)-dependent pathways triggered after activation of TCR, the target of R73, warrants clinical investigation in order to assess the potential impact of anti-alpha/beta-TCR mAb on CsA-based immunosuppressive regimens.

Pretransplant test-dose pharmacokinetic profiles were used to determine individual cyclosporine drug bioavailability and clearance rates in renal transplant patients. Assuming a linear relation between dose and area under the concentration curve (AUC), starting i.v. and p.o. CsA doses were computed from the test-dose results. Target values were 400 ng/ml steady-state concentration (Css) during continuous intravenous infusion, and 500 ng/ml average drug concentration (Cavss = AUC/dosing interval) after oral administration, based upon measurements with the specific monoclonal antibody 3H-tracer radioimmunoassay. The outcomes after dose individualization with a 1-(n = 32), 2-(n = 38), or 3-(n = 41) hr i.v. infusion test dose and a p.o. test dose (n = 111) were compared with 228 historical control patients who received a uniform protocol of CsA i.v. at 2.5 mg/kg/day and p.o. at 14 mg/kg/day. The observed Css after i.v. CsA was within 10% of the target concentration in 73% of recipients tested with the 3-hr protocol, a significantly greater fraction than achieved with either the uniform dose (14%), or the 1-(34%) and 2-(25%) hr protocols. Patients in the 3-hr protocol group showed reduced incidences of delayed graft function, early graft loss, and rejection episodes, and a lower mean serum creatinine value, particularly at 7 but also at 30 days posttransplantation. Administration of the predicted oral dose produced a peak concentration of greater than or equal to 700 ng/ml drug absorption in 60% of recipients at 3 days, 90% at 5 days, and 98% at 7 days. The test-dose method less effectively predicted the appropriate oral CsA dose to produce target Cssav and failed to reduce the 90-day rejection incidence. Despite its limitations with the more-complicated p.o. route, the test-dose method successfully predicts i.v. CsA doses, thereby reducing the incidence of early adverse events.

Vascular occlusion of one of the transplanted kidneys represents a potential complication following en bloc transplantation of two pediatric kidneys into adults. Serial renal scans with Tc-99m DTPA, performed on a 26-year-old woman who underwent en bloc transplantation, revealed good perfusion and function of both kidneys in the early postoperative period but acute loss of perfusion and function in one kidney on the ninth postoperative day. Surgical exploration and open biopsy excluded rejection and twisting of the vascular pedicle as possible causes for the acute loss of perfusion and function in this kidney