Ibrutinib in Steroid-Refractory Chronic Graft-versus-Host Disease, a Single-Center Experience.

Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality after allogenic hematopoietic stem cell transplantation. Corticosteroid-based therapies are a mainstay of its initial treatment but there is no consensus in how to treat steroid-refractory cGVHD. Ibrutinib is a Bruton tyrosine kinase and IL-2-inducible kinase inhibitor thought to affect pathways driving cGVHD, and it was approved for the treatment of refractory cGVHD by the Food and Drug Administration (FDA) in August 2017 after a landmark phase 1b/2 study. It was the first medication approved for this indication, but how to best treat refractory cGVHD remains an open question, and there has been limited literature on ibrutinib after the FDA approval. This study sought to characterize the utilization and outcomes associated with ibrutinib use in cGVHD via a retrospective single-center study. Fifty-three patients were identified as having been treated with ibrutinib for cGVHD following FDA approval between September 1, 2017, and December 31, 2020, using an institutional data repository. Their records were reviewed for demographics, cGVHD characteristics, and outcomes. For the entire cohort, two-year overall survival was 76% (95% confidence interval [CI], 60% to 86%), with a median follow-up among survivors of 26 months (range, 1.3 to 39.5 months). However, the 2-year failure-free survival (FFS) after initiation of ibrutinib was 9% (95% CI, 2.6% to 20%), and the median FFS was 4.5 months (95% CI, 2.8 to 7.1 months). Events of FFS included treatment change due to lack of response or toxicity, malignant relapse, or non-treatment related mortality. At the time of this report, 11 patients (21%) remained on ibrutinib. At the time of the FFS event or last follow-up, 6 patients (12%) had a complete or partial response, 34 (64%) had stable disease, and 13 (25%) had progressive disease. Ibrutinib use was associated with no reduction in corticosteroid dose between ibrutinib initiation and FFS event or last follow-up (mean difference, 0.00; P = .98). The most frequently used noncorticosteroid cGVHD therapy after ibrutinib was ruxolitinib (n = 14; 33%). The most common adverse events associated with treatment discontinuation were infection (lung, skin, enterocolitis; n = 6), bleeding and bruising (hematoma, epistaxis, gastrointestinal bleed; n = 5), and muscle aches (n = 2). In a real-world setting, ibrutinib is associated with a modest response rate and FFS and its use in a narrower, more targeted patient population may be indicated.

A minimalist electronic health record-based intervention to reduce standing lab utilisation.

BACKGROUND: Repetitive laboratory testing in stable patients is low-value care. Electronic health record (EHR)-based interventions are easy to disseminate but can be restrictive. OBJECTIVE: To evaluate the effect of a minimally restrictive EHR-based intervention on utilisation. SETTING: One year before and after intervention at a 600-bed tertiary care hospital. 18 000 patients admitted to General Medicine, General Surgery and the Intensive Care Unit (ICU). INTERVENTION: Providers were required to specify the number of times each test should occur instead of being able to order them indefinitely. MEASUREMENTS: For eight tests, utilisation (number of labs performed per patient day) and number of associated orders were measured. RESULTS: Utilisation decreased for some tests on all services. Notably, complete blood count with differential decreased 9% (p<0.001) on General Medicine and 21% (p<0.001) in the ICU. CONCLUSIONS: Requiring providers to specify the number of occurrences of labs changes significantly reduces utilisation in some cases.

E-HeaRT BPA: electronic health record telemetry BPA.

INTRODUCTION: Continuous cardiac monitoring in non-critical care settings is expensive and overutilised. As such, it is an important target of hospital interventions to establish cost-effective, high-quality care. Since inappropriate telemetry use was persistently elevated at our institution, we devised an electronic best practice alert (BPA) and tested it in a randomised controlled fashion. METHODS: Between 4 March 2018 and 5 July 2018 at our 600-bed academic hospital, all non-critical care patients who had at least one telemetry order were randomised to the control or intervention group. The intervention group received daily BPAs if telemetry was active. RESULTS: 275 and 283 patients were randomised to the intervention and control groups, respectively. The intervention group triggered 1042 alerts and trended toward fewer telemetry days (3.8 vs 5.0, p=0.017). The intervention group stopped telemetry 31.7% of the alerted patient-days compared with 23.3% for the control group (OR 1.53, 95% CI 1.24 to 1.88, p<0.001). There were no significant differences in length of stay, rapid responses, code blues, or mortality between the two groups. CONCLUSIONS: Using a randomised controlled design, we show that BPAs significantly reduce telemetry without negatively affecting patient outcomes. They should have a role in promoting high-value telemetry use.

Histologic Case Definition of an Atypical Glomerular Immune-Complex Deposition Following Kidney Transplantation.

INTRODUCTION: Immune-complex deposition in the transplanted kidney can present as well-phenotyped recurrent or de novo glomerular disease. However, a subset, herein termed immune-complex glomerulopathy not otherwise specified (ICG-NOS), defies classification. We quantified, categorized, and characterized cases of transplant ICG-NOS occurring at a single US academic medical center. METHODS: We retrospectively reviewed our single-institution pathology database (July 2007-July 2018) to identify and categorize all cases of immune-complex deposition in kidney allografts (based on immunofluorescence microscopy). We extracted clinicopathologic and outcome data for ICG-NOS (i.e., immune complex deposition not conforming to any well-characterized glomerular disease entity). RESULTS: Of 104 patients with significant immune deposits, 28 (27%) were classified as ICG-NOS. We created 5 mutually exclusive ICG-NOS categories: Full-house, Quasi-full-house, IgA-rich, C1q-rich, and C1q-poor. Overall, 16 (57%) patients met criteria for definite or possible allograft rejection, including 9 (32%) with antibody-mediated rejection (ABMR), 3 (11%) suspicious for ABMR, 1 (4%) with T-cell-mediated rejection (TCMR), and 9 (32%) with borderline TCMR. After a median follow-up of 2.3 (range, 0.1-14.0) years after biopsy, 7 (25%) allografts had failed and an additional 8 (29%) had persistent renal dysfunction (hematuria, 14%; proteinuria, 21%; and estimated glomerular filtration rate <60 ml/min per 1.73 m2, 11%). CONCLUSION: In contrast to prior studies, our findings suggest that ICG-NOS is not necessarily a benign glomerular process and that there may be an association between ICG-NOS and alloimmunity. Our immunofluorescence-based classification provides a framework for future studies aiming to further elucidate ICG-NOS pathogenesis and prognosis.

Recurrence of FSGS after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: FSGS recurrence after kidney transplantation is a major risk factor for graft loss. However, the natural history, clinical predictors, and response to treatment remain unclear because of small sample sizes and poor generalizability of single-center studies, and disease misclassification in registry-based studies. We therefore aimed to determine the incidence, predictors, and treatment response of recurrent FSGS in a large cohort of kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Post-Transplant Glomerular Disease (TANGO) project is an observational, multicenter, international cohort study that aims to investigate glomerular disease recurrence post-transplantation. Transplant recipients were screened for the diagnosis of idiopathic FSGS between 2005 and 2015 and details were recorded about the transplant, clinical outcomes, treatments, and other risk factors. RESULTS: Among 11,742 kidney transplant recipients screened for FSGS, 176 had a diagnosis of idiopathic FSGS and were included. FSGS recurred in 57 patients (32%; 95% confidence interval [95% CI], 25% to 39%) and 39% of them lost their graft over a median of 5 (interquartile range, 3.0-8.1) years. Multivariable Cox regression revealed a higher risk for recurrence with older age at native kidney disease onset (hazard ratio [HR], 1.37 per decade; 95% CI, 1.09 to 1.56). Other predictors were white race (HR, 2.14; 95% CI, 1.08 to 4.22), body mass index at transplant (HR, 0.89 per kg/m2; 95% CI, 0.83 to 0.95), and native kidney nephrectomies (HR, 2.76; 95% CI, 1.16 to 6.57). Plasmapheresis and rituximab were the most frequent treatments (81%). Partial or complete remission occurred in 57% of patients and was associated with better graft survival. CONCLUSIONS: Idiopathic FSGS recurs post-transplant in one third of cases and is associated with a five-fold higher risk of graft loss. Response to treatment is associated with significantly better outcomes but is achieved in only half of the cases.

Integrating Adjuvant Analgesics into Perioperative Pain Practice: Results from an Academic Medical Center.

BACKGROUND: Opioid-sparing postoperative pain management therapies are important considering the opioid epidemic. Total knee arthroplasty (TKA) is a common and painful procedure accounting for a large number of opioid prescriptions. Adjuvant analgesics, nonopioid drugs with primary indications other than pain, have shown beneficial pain management and opioid-sparing effects following TKA in clinical trials. We evaluated the adjuvant analgesic gabapentin for its usage patterns and its effects on opioid use, pain, and readmissions. METHODS: This retrospective, observational study included 4,046 patients who received primary TKA between 2009 and 2017 using electronic health records from an academic tertiary care medical institute. Descriptive statistics and multivariate modeling were used to estimate associations between inpatient gabapentin use and adverse pain outcomes as well as inpatient oral morphine equivalents per day (OME). RESULTS: Overall, there was an 8.72% annual increase in gabapentin use (P < 0.001). Modeled estimates suggest that gabapentin is associated with a significant decrease in opioid consumption (estimate = 0.63, 95% confidence interval = 0.49-0.82, P < 0.001) when controlling for patient characteristics. Patients receiving gabapentin had similar discharge pain scores, follow-up pain scores, and 30-day unplanned readmission rates compared with patients receiving no adjuvant analgesics (P > 0.05). CONCLUSIONS: When assessed in a real-world setting over a large cohort of TKA patients, gabapentin is an effective pain management therapy that is associated with reduced opioid consumption-a national priority in this time of opioid crisis-while maintaining the same quality of pain management.

Home Dialysis in the Prospective Payment System Era.

The ESRD Prospective Payment System introduced two incentives to increase home dialysis use: bundling injectable medications into a single payment for treatment and paying for home dialysis training. We evaluated the effects of the ESRD Prospective Payment System on home dialysis use by patients starting dialysis in the United States from January 1, 2006 to August 31, 2013. We analyzed data on dialysis modality, insurance type, and comorbidities from the United States Renal Data System. We estimated the effect of the policy on home dialysis use with multivariable logistic regression and compared the effect on Medicare Parts A/B beneficiaries with the effect on patients with other types of insurance. The ESRD Prospective Payment System associated with a 5.0% (95% confidence interval [95% CI], 4.0% to 6.0%) increase in home dialysis use by the end of the study period. Home dialysis use increased by 5.8% (95% CI, 4.3% to 6.9%) among Medicare beneficiaries and 4.1% (95% CI, 2.3% to 5.4%) among patients covered by other forms of health insurance. The difference between these groups was not statistically significant (1.8%; 95% CI, -0.2% to 3.8%). Conversely, in both populations, the training add-on did not associate with increases in home dialysis use beyond the effect of the policy. The ESRD Prospective Payment System bundling, but not the training add-on, associated with substantial increases in home dialysis, which were identical for both Medicare and non-Medicare patients. These spill-over effects suggest that major payment changes in Medicare can affect all patients with ESRD.

A Transcription Factor Pulse Can Prime Chromatin for Heritable Transcriptional Memory.

Short-term and long-term transcriptional memory is the phenomenon whereby the kinetics or magnitude of gene induction is enhanced following a prior induction period. Short-term memory persists within one cell generation or in postmitotic cells, while long-term memory can survive multiple rounds of cell division. We have developed a tissue culture model to study the epigenetic basis for long-term transcriptional memory (LTTM) and subsequently used this model to better understand the epigenetic mechanisms that enable heritable memory of temporary stimuli. We find that a pulse of transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα) induces LTTM on a subset of target genes that survives nine cell divisions. The chromatin landscape at genes that acquire LTTM is more repressed than at those genes that do not exhibit memory, akin to a latent state. We show through chromatin immunoprecipitation (ChIP) and chemical inhibitor studies that RNA polymerase II (Pol II) elongation is important for establishing memory in this model but that Pol II itself is not retained as part of the memory mechanism. More generally, our work reveals that a transcription factor involved in lineage specification can induce LTTM and that failure to rerepress chromatin is one epigenetic mechanism underlying transcriptional memory.