Physician adjudication of angioedema diagnosis codes in a population of patients with heart failure prescribed angiotensin-converting enzyme inhibitor therapy.

PURPOSE: Our objective was to calculate the positive predictive value (PPV) of the ICD-9 diagnosis code for angioedema when physicians adjudicate the events by electronic health record review. Our secondary objective was to evaluate the inter-rater reliability of physician adjudication. METHODS: Patients from the Cardiovascular Research Network previously diagnosed with heart failure who were started on angiotensin-converting enzyme inhibitors (ACEI) during the study period (July 1, 2006 through September 30, 2015) were included. A team of two physicians per participating site adjudicated possible events using electronic health records for all patients coded for angioedema for a total of five sites. The PPV was calculated as the number of physician-adjudicated cases divided by all cases with the diagnosis code of angioedema (ICD-9-CM code 995.1) meeting the inclusion criteria. The inter-rater reliability of physician teams, or kappa statistic, was also calculated. RESULTS: There were 38 061 adults with heart failure initiating ACEI in the study (21 489 patient-years). Of 114 coded events that were adjudicated by physicians, 98 angioedema events were confirmed for a PPV of 86% (95% CI: 80%, 92%). The kappa statistic based on physician inter-rater reliability was 0.65 (95% CI: 0.47, 0.82). CONCLUSIONS: ICD-9 diagnosis code of 995.1 (angioneurotic edema, not elsewhere classified) is highly predictive of angioedema in adults with heart failure exposed to ACEI.

Comparison of a Kidney Replacement Therapy Risk Score Developed in Kaiser Permanente Northwest vs Estimated Glomerular Filtration Rate in Advanced Chronic Kidney Disease Using Decision Curve Analysis.

INTRODUCTION: Use of kidney replacement therapy (KRT) prediction models for guiding arteriovenous fistula (AVF) referrals in advanced chronic kidney disease (CKD) is unknown. We aimed to compare a hypothetical approach using a KRT prediction model developed in Kaiser Permanente Northwest to estimated glomerular filtration rate (eGFR) for AVF referrals. METHODS: Our retrospective cohort consisted of patients with stage G4 CKD in Kaiser Permanente Northwest followed by nephrology. Two-year KRT risk was calculated at each nephrology visit up to 2 years from entrance into cohort based on a previously published model. We calculated sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) based on several 2-year KRT risk and eGFR cutoffs for outcome of hemodialysis at 18 months. We compared an approach of AVF referral using 2-year KRT risk and eGFR cutoffs using decision curve analysis. RESULTS: Two-year KRT risk better discriminated progression to hemodialysis compared to eGFR < 15 mL/min (AUC 0.60 vs 0.69 at 2-year KRT risk > 20% and 0.69 at 2-year KRT risk > 40%, p = 0.003 and 0.006, respectively) but not to eGFR of 20 mL/min (AUC 0.64, p = 0.16 and 0.19, respectively). Decision curve analysis showed that AVF referral guided by 2-year KRT risk score resulted in higher net benefit compared to eGFR at low thresholds for referral. CONCLUSION: In stage G4 CKD, a 2-year KRT risk model better predicted progression to KRT at 18 months compared to an eGFR of 15 mL/min but not to 20 mL/min and may improve timely referral for AVF placement in patients at lower thresholds for referral.

Predicted risk of renal replacement therapy at arteriovenous fistula referral in chronic kidney disease.

BACKGROUND AND OBJECTIVES: Optimal timing of arteriovenous fistula placement in chronic kidney disease remains difficult and contributes to high central venous catheter use at initial hemodialysis. We tested whether a prediction model for progression to renal replacement therapy developed at Kaiser Permanente Northwest may help guide decisions about timing of referral for arteriovenous fistula placement. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A total of 205 chronic kidney disease stage 4 patients followed by nephrology referred for arteriovenous fistula placement were followed for up to 2 years. Patients were censored if they died or discontinued Kaiser Permanente Northwest coverage. Survival analyses were performed for overall progression to renal replacement therapy divided by quartiles based on 2-year risk for renal replacement therapy and estimated glomerular filtrate rate at time of referral. RESULTS: By 2 years, 60% progressed to renal replacement therapy and 11% had died. 80% in the highest risk versus 36% in the lowest risk quartile progressed to renal replacement therapy (predicted risk 84% vs 17%). 75% in the lowest estimated glomerular filtrate rate versus 56% in the highest estimated glomerular filtrate rate quartile progressed to renal replacement therapy (mean estimated glomerular filtrate rate 13 mL/min vs 21 mL/min). The hazard ratio was significantly higher for each consecutive higher renal replacement therapy quartile risk while for estimated glomerular filtrate rate, the hazard ratio was only significantly higher for the lowest compared to the highest quartile. The extreme quartile risk ratio was higher for 2-year risk for renal replacement therapy compared to estimated glomerular filtrate rate (4.0 vs 2.4). CONCLUSION: In patients with chronic kidney disease stage 4 referred for arteriovenous fistula placement, 2-year renal replacement therapy risk better discriminated progression to renal replacement therapy compared to estimated glomerular filtrate rate at time of referral.

A Quality Improvement Initiative Targeting Chronic Kidney Disease Metrics Through Increased Urinary Albumin Testing.

INTRODUCTION: Achievement of quality metrics in chronic kidney disease (CKD), specifically urinary albumin testing and angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) use, remained lower in Kaiser Permanente Northwest compared with other Kaiser Permanente regions. We were interested if more frequent testing of urine albumin (ACR) improved CKD quality metrics. METHODS: We implemented a quality improvement project automating ACR testing using an informatics tool in patients with stage 3 CKD linked to an electronic health record (EHR) alert recommending ACEi or ARB initiation in patients with renal indication. RESULTS: At 1 and 2 years after implementation of ACR testing, ACR testing increased from 26.9% prior to implementation to 83% at 1 year and 77% at 2 year after implementation (p < 0.001). However, ACEi or ARB use did not increase significantly (65.8% vs 65.7% vs 66.4%, p = 0.54). There was also no significant change in other quality metrics, including diabetes control, hypertension control, and comanagement of higher-risk CKD patients. DISCUSSION AND CONCLUSION: In patients with stage 3 CKD, increased ACR testing via automated testing linked with EHR alert did not result in an improvement in CKD quality metrics.

Real-Time Gas Mixture Analysis Using Mid-Infrared Membrane Microcavities.

Real-time gas analysis on-a-chip was demonstrated using a mid-infrared (mid-IR) microcavity. Optical apertures for the microcavity were made of ultrathin silicate membranes embedded in a silicon chip using the complementary metal-oxide-semiconductor (CMOS) process. Fourier transform infrared spectroscopy (FTIR) shows that the silicate membrane is transparent in the range of 2.5-6.0 µm, a region that overlaps with multiple characteristic gas absorption lines and therefore enables gas detection applications. A test station integrating a mid-IR tunable laser, a microgas delivery system, and a mid-IR camera was assembled to evaluate the gas detection performance. CH4, CO2, and N2O were selected as analytes due to their strong absorption bands at λ = 3.25-3.50, 4.20-4.35, and 4.40-4.65 µm, which correspond to C-H, C-O, and O-N stretching, respectively. A short subsecond response time and high gas identification accuracy were achieved. Therefore, our chip-scale mid-IR sensor provides a new platform for an in situ, remote, and embedded gas monitoring system.

Association of Proteinuria with Central Venous Catheter Use at Initial Hemodialysis.

CONTEXT: Central venous catheter (CVC) use is associated with increased mortality and complications in hemodialysis recipients. Although prevalent CVC use has decreased, incident use remains high. OBJECTIVE: To examine characteristics associated with CVC use at initial dialysis, specifically looking at proteinuria as a predictor of interest. DESIGN: Retrospective cohort of 918 hemodialysis recipients from Kaiser Permanente Northwest who started hemodialysis from January 1, 2004, to January 1, 2014. MAIN OUTCOME MEASURES: Multivariable logistic regression was used to examine an association of proteinuria with the primary outcome of CVC use. RESULTS: More than one-third (36%) of patients in our cohort started hemodialysis with an arteriovenous fistula, and 64% started with a CVC. Proteinuria was associated with starting hemodialysis with a CVC (likelihood ratio test, p < 0.001) after adjustment for age, peripheral vascular disease, congestive heart failure, diabetes, sex, race, and length of predialysis care. However, on pairwise comparison, only patients with midgrade proteinuria (0.5-3.5 g) had lower odds of starting hemodialysis with a CVC (odds ratio = 0.39, 95% confidence interval = 0.24-0.65). CONCLUSION: Proteinuria was associated with use of CVC at initial hemodialysis. However, a graded association did not exist, and only patients with midgrade proteinuria had significantly lower odds of CVC use. Our findings suggest that proteinuria is an explanatory finding for CVC use but may not have pragmatic value for decision making. Patients with lower levels of proteinuria may have a higher risk of starting dialysis with a CVC.

Impact of single immunosuppressive drug withdrawal on lymphocyte immunoreactivity.

BACKGROUND: Chronic rejection is a major cause of graft loss in kidney transplant recipients. Nonadherence to drug therapy is a well-recognized cause of chronic rejection leading to long-term graft dysfunction and failure for transplant recipients. Immunosuppressive medications with short half-lives that require frequent dosing, such as tacrolimus, complicate transplant regimens and may increase noncompliance. Regimens could be simplified using drugs with long half-lives requiring once-daily administration, such as sirolimus. The impact of missing doses of single agents has not been studied extensively. Erratic compliance or temporary discontinuation of immunosuppressive drugs may have significant implications for chronic rejection. METHODS: Our study evaluated the impact of single drug withdrawal of commonly used immunosuppressive agents (sirolimus and tacrolimus) on lymphocyte responses. We analyzed lymphocyte proliferation, cytokine secretion, and adenosine triphosphate generation using a crossover study design with normal healthy patients. Lymphocyte proliferation was assessed using 5-bromo-2-deoxyuridine incorporation, and T cell function was analyzed by examining adenosine triphosphate generation. RESULTS: Our results indicate that sirolimus exerts prolonged suppression of lymphocyte proliferation and decreased interleukin 17A that lasts up to 48 h after drug withdrawal. In comparison, tacrolimus did not have a similar effect on lymphocyte proliferation or interleukin 17A secretion. CONCLUSION: Future analysis of sirolimus in diverse transplantation populations merits investigation.

Functional outcome of endoscopic plantar fasciotomy.

BACKGROUND: The majority of cases of plantar fasciitis can be treated nonoperatively; however, a small number of patients remain refractory to nonoperative treatment and operative intervention is indicated. Historically, open treatment has been recommended, but more recently endoscopic plantar fasciotomy (EPF) has produced promising results. METHODS: Forty-eight patients (56 feet) were identified who underwent endoscopic plantar fasciotomy. Forty-one patients (49 feet) were available for followup. There were 15 men and 26 women, with an average age of 53.8 (range, 42 to 68) years. The mean followup time was 49.5 (range, 6 to 142) months. An AOFAS Hind foot Scale was used for analysis. The influence of gender, duration of symptoms, severity of symptoms, and bilateral verses unilateral release were examined. RESULTS: Pain resolved completely in 37 feet, decreased in 11 feet, and increased in one foot. The mean postoperative AOFAS Hindfoot score improved 39 points (54 to 93, p < 0.001). Patients with severe symptoms achieved higher mean improvement than the moderate symptom group (p < 0.0001). Patients with symptoms greater than 24~months trended towards lower mean improvement and lower post operative AOFAS Hindfoot scores. Both gender and laterality did not significantly influence outcome. There was one superficial infection, one third and fourth metatarsal stress fracture in the same patient, and transient lateral hindfoot pain in five patients. CONCLUSION: EPF was an effective operation with reproducible results, low complication rate, and little risk of iatrogenic nerve injury with proper technique.

Systems biology approach to transplant tolerance: proof of concept experiments using RNA interference (RNAi) to knock down hub genes in Jurkat and HeLa cells in vitro.

BACKGROUND: Systems biology is gaining importance in studying complex systems such as the functional interconnections of human genes [1]. To investigate the molecular interactions involved in T cell immune responses, we used databases of physical gene-gene interactions to constructed molecular interaction networks (interconnections) with R language algorithms. This helped to identify highly interconnected "hub" genes AT(1)P5C1, IL6ST, PRKCZ, MYC, FOS, JUN, and MAPK1. We hypothesized that suppression of these hub genes in the gene network would result in significant phenotypic effects on T cells and examined this in vitro. The molecular interaction networks were then analyzed and visualized with Cytoscape. MATERIALS AND METHODS: Jurkat and HeLa cells were transfected with siRNA for the selected hub genes. Cell proliferation was measured using ATP luminescence and BrdU labeling, which were measured 36, 72, and 96 h after activation. RESULTS: Following T cell stimulation, we found a significant decrease in ATP production (P < 0.05) when the hub genes ATP5C1 and PRKCZ were knocked down using siRNA transfection, whereas no difference in ATP production was observed in siRNA transfected HeLa cells. However, HeLa cells showed a significant (P < 0.05) decrease in cell proliferation when the genes MAPK1, IL6ST, ATP5C1, JUN, and FOS were knocked down. CONCLUSION: In both Jurkat and HeLa cells, targeted gene knockdown using siRNA showed decreased cell proliferation and ATP production in both Jurkat and HeLa cells. However, Jurkat T cells and HELA cells use different hub genes to regulate activation responses. This experiment provides proof of principle of applying siRNA knockdown of T cell hub genes to evaluate their proliferative capacity and ATP production. This novel concept outlines a systems biology approach to identify hub genes for targeted therapeutics.

Advances of genomic science and systems biology in renal transplantation: a review.

The diagnosis of rejection in kidney transplant patients is based on histologic classification of a graft biopsy. The current "gold standard" is the Banff 97 criteria; however, there are several limitations in classifying rejection based on biopsy samples. First, a biopsy involves an invasive procedure. Second, there is significant variance among blinded pathologists in the interpretation of a biopsy. And third, there is also variance between the histology and the molecular profiles of a biopsy. To increase the positive predictive value of classifiers of rejection, a Banff committee is developing criteria that integrate histologic and molecular data into a unified classifier that could diagnose and prognose rejection. To develop the most appropriate molecular criteria, there have been studies by multiple groups applying omics technologies in attempts to identify biomarkers of rejection. In this review, we discuss studies using genome-wide data sets of the transcriptome and proteome to investigate acute rejection, chronic allograft dysfunction, and tolerance. We also discuss studies which focus on genetic biomarkers in urine and peripheral blood, which will provide clinicians with minimally invasive methods for monitoring transplant patients. We also discuss emerging technologies, including whole-exome sequencing and RNA-Seq and new bioinformatic and systems biology approaches, which should increase the ability to develop both biomarkers and mechanistic understanding of the rejection process.

Abdominal insufflation decreases blood loss and mortality after porcine liver injury.

BACKGROUND: Uncontrolled intra-abdominal bleeding is a common cause of death in trauma patients in the prehospital and perioperative settings. The detrimental effects of abdominal hypertension are well studied, but the potential therapeutic use of abdominal insufflation for hemostasis has not been fully explored. We measured the effect of abdominal insufflation on blood loss and physiologic outcomes in a swine model of blunt liver injury. METHODS: Twenty-one anticoagulated swine (32 +/- 3 kg) were anesthesized; laparotomy was performed to localize liver anatomy and to place loose tourniquettes isolating the porta hepatis and supra/infrahepatic vena cava. A captive bolt gun was used to create a grade V hepatic laceration, producing massive parenchymal injury as well as complex tears of the middle and right hepatic veins. Animals were randomized into either control (n = 10) or abdominal insufflation at 20 cm H(2)O pressure (n = 11) groups. Crystalloid was used to maintain a mean arterial pressure of 30 mm Hg. Arterial pressure and other physiologic variables were recorded for 20 minutes. Animals were then sacrificed and blood loss measured. RESULTS: Blood loss was 69% lower in insufflated animals compared with controls (384 +/- 51 versus 1252 +/- 88 cc, p < 0.001). After 20 minutes, insufflated animals had significantly higher mean arterial blood pressure (32.2 +/- 4.2 versus 21.2 +/- 4.0 mm Hg) and lower total resuscitation volume (195 +/- 83 versus 1356 +/- 95 cc). Three pigs died in the control group (30%), whereas no insufflated animals died (p < 0.05). CONCLUSION: In a swine model of catastrophic blunt hepatic injury, abdominal insufflation significantly decreased blood loss and mortality.

Bypassing V1: a direct geniculate input to area MT.

Thalamic nuclei are thought to funnel sensory information to the brain's primary cortical areas, which in turn transmit signals afresh to higher cortical areas. Here we describe a direct projection in the macaque monkey from the lateral geniculate nucleus (LGN) to the motion-selective middle temporal area (MTor V5), a cortical area not previously considered 'primary'. The constituent neurons are mostly koniocellular, send virtually no collateral axons to primary visual cortex (V1) and equal about 10% of the V1 population innervating MT. This pathway could explain the persistence of motion sensitivity in subjects following injury to V1, suggesting more generally that residual perception after damage in a primary area may arise from sparse thalamic input to 'secondary' cortical areas.