Communication between hospitalists and primary care providers (PCPs) upon discharge has been much discussed, but the transition from outpatient to inpatient has received less attention. We questioned whether a brief, standardized e-mail from the hospitalist to the PCP upon admission could facilitate information exchange, increase communication, elucidate PCP preferences, and improve outcomes.This prospective single-center study with a preintervention-to-postintervention design involved 300 inpatient admissions from June 2015 through October 2015 in the Veterans Affairs Connecticut Healthcare System. Hospitalists e-mailed an encrypted notification of admission along with standardized questions to PCPs within 1 day of admission. Measurements included the number of communications between PCPs and hospitalists, length of stay (LOS), 30-day readmissions, 30-day emergency department (ED) utilization rates, PCP preferences with regard to communication, and follow-up.Preintervention data for 94 patients during a 6-week period revealed 0.11 communications per patient, an LOS of 4.18 days, 30-day readmissions of 28.7%, and 30-day ED visits of 32%. Postintervention data on 206 patients during the next 12 weeks showed statistically significant increased communications per patient (0.5), and a nonsignificant decrease in LOS (3.96 days), 30-day readmissions (22.3%), and 30-day ED visits (31%). P values were <0.001, 0.67, 0.4, and 0.79, respectively. PCPs preferred e-mail communication upon discharge (40%) to telephone (25%) or instant messaging (13%), and 39% wanted a follow-up appointment within 2 weeks, regardless of what transpired.A hospitalist-led transition-of-care intervention designed to improve communication and information exchange between PCPs and hospitalists at the time of admission demonstrated that encrypted e-mail could be used as a tool to obtain useful additional medical and psychosocial information and to better understand PCP attitudes and preferences. The increased level of communication did not yield statistically significant decreases in LOS, 30-day readmission rates, or 30-day post-discharge ED visits, however.
424 Immunohistochemical measures of vascular endothelial growth factor (VEGF) expression in pancreatic cancer have typically been qualitative or semi-quantitative. Furthermore, VEGF levels in primary versus metastatic sites are not well characterized. We have recently developed a set of algorithms called automated quantitative analysis (AQUA) that can assess tissue microarrays (TMA) using fluorescent tags to define tumors, localize sub-cellular compartments, and grade intensity of specific markers on a continuous scale. Our purpose was to use AQUA to compare VEGF levels on a pancreatic cancer TMA containing tumors removed from pancreas and metastatic sites. TMAs were constructed by arraying 1.5-mm cores from 80 cases of pancreatic adenocarcinoma (1996-2002) obtained from the archives of the Yale Dept. of Pathology. Fourteen normal pancreatic cores served as controls. Staining for AQUA is similar to standard immunohistochemistry and involves antigen retrieval and application of primary antibodies, but with epifluorescence detection. Slides are then counterstained with DAPI for nuclear and cytokeratin for membrane visualization. Primary antibodies used were VEGF specific for isoforms 165, 189, and 206 (BD Pharmingen) and cytokeratin (DAKO). Of the 80 cases on the TMA, 58 were evaluable, of which 35, 9, and 14 were from pancreas, liver, and other intraabdominal contiguous or metastatic sites, respectively. Mean VEGF expression of malignant tissue (score 32.8) was similar to that of normal pancreatic tissue (score 29.9; p=0.43 two-tailed student’s t-test). Mean VEGF expression in extratumoral, stromal compartments, however, was lower in malignant spots (score 6.9) compared to normal pancreas (score 17.6; p=0.00042). VEGF expression among the different cancer sites did not differ significantly with the exception of pancreas (score 33.5) compared to non-hepatic contiguous or metastatic sites (score 26.3; p=0.038). In conclusion, VEGF expression was similar in normal pancreatic and malignant tissue as measured by quantitative immunohistochemistry. Stromal VEGF expression however, appeared to be lower in malignant tissue than in normal pancreas, and tumor expression of VEGF was lower in non-hepatic contiguous or metastatic sites compared with primary pancreatic cancers. Further evaluation will be performed on an expanded cohort of patients and correlated with clinical outcome.
Renalase, a novel secretory flavoprotein with amine oxidase activity, is secreted into the blood by the kidneys and is hypothesized to participate in blood pressure (BP) regulation. We investigated the associations of renalase with BP and the risk of hypertension by examining renalase single nucleopeptide polymorphism (SNPs), serum renalase levels, and renal expression of renalase in humans.① Subjects (n = 514) from the original Baoji Salt-Sensitive Study cohort were genotyped to investigate the association of renalase SNPs with longitudinal BP changes and the risk of hypertension during 14 years of follow-up. ② Two thousand three hundred and ninety two participants from the Hanzhong Adolescent Hypertension Study cohort were used to examine the association of serum renalase levels with hypertension. Renalase expression in renal biopsy specimens from 193 patients were measured by immunohistochemistry. ③ Renalase expression was compared in hypertensive vs. normotensive patients.① SNP rs7922058 was associated with 14-year change in systolic BP, and rs10887800, rs796945, rs1935582, rs2296545, and rs2576178 were significantly associated with 14-year change in diastolic BP while rs1935582 and rs2576178 were associated with mean arterial pressure change over 14 years. In addition, SNPs rs796945, rs1935582, and rs2576178 were significantly associated with hypertension incidence. Gene-based analysis found that renalase gene was significantly associated with hypertension incidence over 14-year follow-up after adjustment for multiple measurements. ② Hypertensive subjects had higher serum renalase levels than normotensive subjects (27.2 ± 0.4 vs. 25.1 ± 0.2 μg/mL). Serum renalase levels and BPs showed a linear correlation. In addition, serum renalase was significantly associated with the risk of hypertension [OR = 1.018 (1.006-1.030)]. ③ The expression of renalase in human renal biopsy specimens significantly decreased in hypertensive patients compared to non-hypertensive patients (0.030 ± 0.001 vs. 0.038 ± 0.004).These findings indicate that renalase may play an important role in BP progression and development of hypertension.
Objective: Elevated blood pressure (BP) in childhood is associated with adult hypertension and arterial stiffness. We aimed to determine the independent association of time in target range (TTR) for systolic blood pressure (SBP) from childhood to midlife with arterial stiffness in midlife. Design and method: Using data from the ongoing cohort of Hanzhong Adolescent Hypertension study, 1959 children and adolescents aged 6 to 18 years were enrolled at baseline. We assessed SBP-TTR from childhood to adulthood for 36 years, with the target range of SBP defined as 90th – 95th percentile for age, sex, and height in childhood, and 110 to 130 mmHg in adulthood. Results: During the 36 years of follow-up, the risk of arterial stiffness gradually decreased with increasing TTR for SBP. After fully adjustment for traditional cardiovascular risk factors, comparing the highest vs. lowest quartiles of TTR for SBP, the odds ratios (ORs) [95% confidence intervals (CIs)] were 0.642 (0.452-0.911) for the risk of arterial stiffness in adulthood. TTR remained significantly associated with arterial stiffness despite adjustment for mean SBP or SBP variability. In addition, males with highest quartile of SBP-TTR was significantly associated with a decreased risk of arterial stiffness [OR 95% CI, 0.432 (0.262-0.710)], while no significant difference was found in females compared with the lowest TTR group. Conclusions: Higher long-term TTR for SBP from childhood to adulthood was associated with a decreased risk of arterial stiffness in adulthood independent of mean BP or BP variability. Therefore, SBP-TTR from an early age might serve as a modifiable risk factor for future cardiovascular diseases in later life.
Objective: Vascular aging, as assessed by structural and functional arterial properties, is an independent predictor of cardiovascular outcomes. In this study, we aimed to investigate the potential associations of ultra long-term blood pressure (BP) variability from childhood to adulthood with vascular aging in midlife. Design and method: Using data from the ongoing cohort of Hanzhong Adolescent Hypertension study, 2065 participants aged 6 to 18 years at baseline were followed up with seven visits over 30 years. Long-term BP variability was defined as the standard deviation (SD) and average real variability (ARV) of BP over 30 years (seven visits). Vascular aging included arterial stiffness, carotid hypertrophy, and carotid plaque. Results: Over 30 years of follow-up, 444 of the 2065 participants developed arterial stiffness. After adjusting for demographic variables, clinical characteristics and mean BP over 30 years, higher SDSBP, ARVSBP, SDDBP and ARVDBP from childhood to midlife were significantly associated with arterial stiffness in midlife. Additionally, higher SDDBP was associated with risk of carotid hypertrophy. Greater SDDBP and ARVDBP were significantly associated with the presence of carotid plaque in midlife. When we used cumulative exposure to BP from childhood to adulthood instead of mean BP as adjustment factors, results were similar. Furthermore, we found a significant correlation between long-term BP variability from youth to adulthood and arterial stiffness, while long-term BP variability from childhood to adolescence is associated with the presence of carotid plaques. The subpopulation treatment effect pattern plot methodology demonstrated a progressive divergence in the risk of vascular aging during midlife between the high SDSBP or high ARVSBP group and the low SDSBP or low ARVSBP group as age increases. Notably, this divergence became particularly pronounced in a subpopulation of individuals around the age of 44. Conclusions: Higher BP variability from childhood to adulthood may increase the risk of vascular aging in midlife independently of mean BP or cumulative BP exposure. Therefore, long-term BP variability from an early age may serve as a predictor of cardiovascular diseases in later life.
AKI is characterized by increased catecholamine levels and hypertension. Renalase, a secretory flavoprotein that oxidizes catecholamines, attenuates ischemic injury and the associated increase in catecholamine levels in mice. However, whether the amine oxidase activity of renalase is involved in preventing ischemic injury is debated. In this study, recombinant renalase protected human proximal tubular (HK-2) cells against cisplatin- and hydrogen peroxide-induced necrosis. Similarly, genetic depletion of renalase in mice (renalase knockout) exacerbated kidney injury in animals subjected to cisplatin-induced AKI. Interestingly, compared with the intact renalase protein, a 20-amino acid peptide (RP-220), which is conserved in all known renalase isoforms, but lacks detectable oxidase activity, was equally effective at protecting HK-2 cells against toxic injury and preventing ischemic injury in wild-type mice. Furthermore, in vitro treatment with RP-220 or recombinant renalase rapidly activated Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinases and downregulated c-Jun N-terminal kinase. In summary, renalase promotes cell survival and protects against renal injury in mice through the activation of intracellular signaling cascades, independent of its ability to metabolize catecholamines, and we have identified the region of renalase required for these effects. Renalase and related peptides show potential as therapeutic agents for the prevention and treatment of AKI.
Background An increased risk for developing essential hypertension, stroke and diabetes is associated with single nucleotide gene polymorphisms in renalase, a newly described secreted flavoprotein with oxidoreductase activity. Gene deletion causes hypertension, and aggravates acute ischemic kidney (AKI) and cardiac injury. Independent of its intrinsic enzymatic activities, extracellular renalase activates MAPK signaling and prevents acute kidney injury (AKI) in wild type (WT) mice. Therefore, we sought to identity the receptor for extracellular renalase. Methods and Results RP-220 is a previously identified, 20 amino acids long renalase peptide that is devoid of any intrinsic enzymatic activity, but it is equally effective as full-length recombinant renalase at protecting against toxic and ischemic injury. Using biotin transfer studies with RP-220 in the human proximal tubular cell line HK-2 and protein identification by mass spectrometry, we identified PMCA4b as a renalase binding protein. This previously characterized plasma membrane ATPase is involved in cell signaling and cardiac hypertrophy. Co-immunoprecipitation and co-immunolocalization confirmed protein-protein interaction between endogenous renalase and PMCA4b. Down-regulation of endogenous PMCA4b expression by siRNA transfection, or inhibition of its enzymatic activity by the specific peptide inhibitor caloxin1b each abrogated RP-220 dependent MAPK signaling and cytoprotection. In control studies, these maneuvers had no effect on epidermal growth factor mediated signaling, confirming specificity of the interaction between PMCA4b and renalase. Conclusions PMCA4b functions as a renalase receptor, and a key mediator of renalase dependent MAPK signaling.
Abstract Although the National Kidney Foundation (NKF) has published clinical practice guidelines for the management of risk factors for cardiovascular disease, these guidelines have not been tested rigorously for their effectiveness. We conducted an observational study among patients with end‐stage kidney disease to examine the prognostic impact of threshold levels recommended by the NKF for blood pressure, hemoglobin, calcium‐phosphate product, parathyroid hormone, low‐density lipoprotein, and glycosylated hemoglobin. The study population (N=197) was assembled from a previously completed randomized trial examining arteriovenous graft thrombosis. Cox proportional hazard analysis was used to calculate hazard ratios for the association of levels outside guideline recommended targets and death, adjusting for age, comorbidity, race, and albumin. The proportion of patients outside guideline targets ranged from 33% to 81%, and the impact of levels outside guideline targets on mortality varied substantially. Elevated calcium‐phosphate product and glycosylated hemoglobin had harmful effects, with adjusted hazard ratios of 1.58 (95% CI 1.00–2.50; p=0.050) and 2.21 (95% CI 0.99–4.97; p=0.054), respectively. Nontarget levels for blood pressure, hemoglobin, and parathyroid hormone had little effect, with adjusted hazard ratios of 1.15 (95% CI 0.74–1.78; p=0.542), 1.04 (95% CI 0.65–1.68; p=0.866), and 0.90 (95% CI 0.50–1.61; p=0.722), respectively. Elevated low‐density lipoprotein had a paradoxically beneficial effect, with an adjusted hazard ratio of 0.48 (95% CI 0.23–1.00; p=0.049). These results suggest that the prognostic impact of current threshold levels recommended by select NKF guidelines on mortality is variable. Accordingly, the development and implementation of clinical practice guidelines should be accompanied by corresponding efforts to confirm their impact on patient outcomes. Such efforts are essential for the improvement of guidelines and to inform health policy optimally.
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