WAGR, Sex Reversal, Bilateral Gonadoblastomas, and Intralobar Nephrogenic Rests: Uncertainties of Pre-Biopsy Chemotherapy in a High Risk Syndrome for Nephroblastoma.

Background: WT1 deletions are associated with nephroblastomas, WT mutations are associated with 46, XY sex reversal. It is unclear why only a few WT1 deletions are associated with sex reversal. Case report. This 46, XY female had a 15.2 MB interstitial deletion of 11p14.1p11.2, which included WT1 and FSHB. No pathogenic abnormalities were identified in 156 other genes associated with disorders of sexual development. Bilateral gonadoblastomas were incidentally diagnosed at 17 months of age at the time of prophylactic gonadectomies. She was treated without biopsy for bilateral nephroblastomas radiologically identified at 18 months of age. Bilateral partial nephrectomies contained treated intralobular nephrogenic rests. Conclusion: It is unclear why WT1 deletions are less associated with 46, XY sex reversal than WT1 mutations. Treating suspected nephroblastomas without biopsy, even in patients with syndromes associated with bilateral nephroblastomas, may still lead to diagnostic and therapeutic uncertainties.

Current Controversies in Sepsis Management.

The overarching goals of early sepsis management include early recognition, appropriate antibiotic therapy and source control, maintenance of hemodynamic stability, and supportive care of organ dysfunction. Despite increasing awareness of the global burden of sepsis, and general agreement on the goals of management, there is ongoing controversy regarding the implementation of specific treatment strategies to optimize patient outcomes. This article will address five current points of controversy in the management of sepsis and septic shock. These include optimal timing of antibiotics in patients with potential sepsis, the role of glucocorticoids in septic shock, vitamin C as a novel therapy for sepsis, the ideal intravenous fluid for resuscitation, and the optimal balance of fluid resuscitation and vasopressor administration in septic shock. For each of these topics, we review relevant literature, discuss areas of controversy, and present our current approach to management.

Pathology Image of the Month: Prolonged Fever in a Traveler.

A 23 year old Russian male cargo ship crew member arrived in the port of New Orleans after a one month voyage originating in central Africa. During the month at sea, he developed fever up to 103 degrees Fahrenheit which was unsuccessfully managed with the antipyretic, dipyrone. He subsequently developed back and stomach pain, along with diarrhea. Upon the ship's arrival to New Orleans, he was transported to a local hospital where his axillary temperature was 104 degrees Fahrenheit. He was unresponsive, tachycardic and tachypneic with a plasma bicarbonate of 16mmol/L (24-32mmol/L).

Disparities in the Cardiometabolic Impact of Adiposity among African American and Hispanic Adolescents.

As adiposity increases in youth, so does the prevalence of cardiometabolic risk factors (CMRFs). The etiology of adiposity-based chronic disease and CMRFs includes ethnoracial disparities that are rarely considered in current treatment approaches. Precision interventions require further characterization of these disparities among high-risk youth. The objective of this study was to characterize differences in CMRF among African American (AA) and Hispanic (H) adolescents with varying levels of adiposity. A cross-sectional analysis of 2284 adolescents aged 12-17 was conducted using 3-year clinical data from Lifedoc Health. CMRF prevalence were compared using χ2, with logistic regression models (LRM) applied to explore the relationships between exposures (age, sex, ethnoracial group, adiposity) and CMRF outcomes. Prevalence of CMRF rose with increasing adiposity, which was the strongest determinant of risk overall. However, individual risk profiles differed between the two groups, with H having higher prevalence of metabolic syndrome (MetS), higher triglycerides and liver enzymes, and low high-density lipoprotein cholesterol (HDL-c). Meanwhile, AA had higher prevalence of elevated blood pressure (BP) in the overweight category, prediabetes in overweight to severe obesity, and type 2 diabetes in obesity. LRM showed 3.0-fold greater chance of impaired glucose metabolism in AA than H, who were 1.7, 5.9, and 8.3 times more likely to have low HDL-c, high liver enzymes, and high triglycerides, respectively. Overweight/obesity prevalence was very high among AA and H adolescents. Excess adiposity was associated with an increased prevalence of CMRF, with individual risk factors differing between groups as adiposity increased. Research within routine clinical settings is required to better characterize these discrepancies and ameliorate their adverse impact on health in the transition to adulthood.

"To Call or Not to Call" Communication Preferences Among Pediatric Hospital Medicine Team Leaders.

OBJECTIVES: Pediatric Hospital Medicine fellowship programs need to abide by Accreditation Council for Graduate Medical Education requirements regarding communication and supervision. Effective communication is critical for safe patient care, yet no prior research has explored optimal communication practices between residents, fellows, and attending hospitalists. Our objective is to explore communication preferences among pediatric senior residents (SRs), Pediatric Hospital Medicine fellows, and hospitalists on an inpatient team during clinical decision-making. METHODS: We conducted a cross-sectional survey study at 6 institutions nationwide. We developed 3 complementary surveys adapted from prior research, 1 for each population: 200 hospitalists, 20 fellows, and 380 SRs. The instruments included questions about communication preferences between the SR, fellow, and hospitalist during clinical scenarios. We calculated univariate descriptive statistics and examined paired differences in percent agreement using χ2 tests, accounting for clustering by institution. RESULTS: Response rates were: 53% hospitalists; 100% fellows; 39% SRs. Communication preferences varied based on role, scenario, and time of day. For most situations, hospitalists preferred more communication with the fellow overnight and when a patient or family is upset than expressed by fellows (P < .01). Hospitalists also desired more communication between the SR and fellow for an upset patient or family than SRs (P < .01), but all respondents agreed the SR should call the fellow for adverse events. More fellows and hospitalists felt that the SR should contact the fellow before placing a consult compared with SRs (95%, 86% vs 64%). CONCLUSIONS: Hospitalists, fellows, and SRs may have differing preferences regarding communication, impacting supervision, autonomy, and patient safety. Training programs should consider such perspectives when creating expectations and communication guidelines.

Physicians' Views on Utilization of an Electronic Health Record-Embedded Calculator to Assess Risk for Venous Thromboembolism among Medical Inpatients: A Qualitative Study.

Background Venous thromboembolism (VTE) causes preventable in-hospital morbidity. Pharmacologic prophylaxis reduces VTE in at-risk patients but also increases bleeding. To increase appropriate prescribing, a risk calculator to guide prophylaxis decisions was developed. Despite efforts to promote its use, providers accessed it infrequently. Objective This study aimed to understand provider perspectives on VTE prophylaxis and facilitators and barriers to using the risk calculator. Design This is a qualitative study exploring provider perspectives on VTE prophylaxis and the VTE risk calculator. Participants We interviewed attending physicians and advanced practice providers who used the calculator, and site champions who promoted calculator use. Providers were categorized by real-world usage over a 3-month period: low (<20% of the time), moderate (20-50%), or high (>50%). Approach During semistructured interviews, we asked about experiences with VTE, calculator use, perspectives on its implementation, and experiences with other risk assessment tools. Once thematic saturation was reached, transcripts were analyzed using content analysis to identify themes. Results Fourteen providers participated. Five were high utilizers, three were moderate utilizers, and six were low utilizers. Three site champions participated. Eight major themes were identified as follows: (1) ease of use, (2) perception of VTE risk, (3) harms of thromboprophylaxis, (4) overestimation of calculator use, (5) confidence in own ability, (6) underestimation of risk by calculator, (7) variability of trust in calculator, and (8) validation to withhold prophylaxis from low-risk patients. Conclusions While providers found the calculator is easy to use, routine use may be hindered by distrust of its recommendations. Inaccurate perception of VTE and bleeding risk may prevent calculator use.

Defining Supervision Preferences and Roles Within a New Subspecialty: Pediatric Hospital Medicine.

OBJECTIVE: To describe supervision preferences among pediatric hospitalists, Pediatric Hospital Medicine (PHM) fellows, and senior residents (SRs), and to better define the ideal role of a PHM fellow. METHODS: We conducted a cross-sectional survey study at 6 institutions nationwide. We developed 3 complementary surveys, one for each population (hospitalists, fellows, SRs). We calculated univariate descriptive and bivariate statistics for categorical variables using Chi-square tests with the Rao-Scott correction to account for clustering by institution. RESULTS: Survey respondents included 106 of 200 hospitalists (53%), all 20 fellows (100%), and 149 of 380 SRs (39%). Most hospitalists and all fellows preferred the supervising hospitalist to have 3+ years of experience or be fellowship-trained. Nearly all fellows preferred the attending round in-person providing progressive independence; while hospitalists and SRs desired greater attending presence on rounds. Hospitalists and fellows wanted more frequent communication when the attending does not round with the team, and more hospitalists desired at least 2 points of contact regardless of attending presence on rounds. Fifty-five percent of SRs reported experiencing much less/less autonomy when on with a fellow than when supervised by a hospitalist only. Regarding the fellow's role, most participants agreed SRs should lead rounds and contact the fellow first with questions. The majority agreed teaching should be a shared responsibility but lacked consensus about how to provide feedback. CONCLUSIONS: Study results reveal preferences about supervising fellows in this new subspecialty. Hospitalists, fellows, and SRs may have differing opinions regarding workflow, communication, and teaching, impacting team leadership and autonomy.

Rapamycin regulates endothelial cell migration through regulation of the cyclin-dependent kinase inhibitor p27Kip1.

Rapamycin is a macrolide antibiotic that inhibits vascular smooth muscle cell proliferation and migration and that is used clinically on drug-eluting stents to inhibit in-stent restenosis. Although inhibition of cell migration is an asset in preventing restenosis, it also leads to impaired stent endothelialization, a significant limitation of current drug-eluting stent technology that necessitates prolonged antiplatelet therapy. We measured the ability of rapamycin to inhibit the migration of human umbilical vein endothelial cells (HUVECs) and human coronary artery endothelial cells (HCAEC) toward the chemoattractant vascular endothelial cell growth factor. Although acute administration of rapamycin had no effect, exposure for 24 h inhibited HUVEC and HCAEC migration. Disruption of the mTORC2 via small interfering RNA was also effective in inhibiting HCAEC migration. Treatment of HCAECs for this period with rapamycin produced an increase in the cyclin-dependent kinase inhibitor p27(Kip), through a decrease in the targeting of the protein for degradation by phosphorylation at Thr(187). ECs isolated from a knock-in mouse expressing p27(Kip1) with a mutation of this residue to an alanine, blocking this phosphorylation, exhibited reduced migration compared with wild-type controls. Silencing of p27(Kip1) with small interfering RNA blocked the effects of rapamycin on migration and tube formation as well as RhoA activation and cytoskeletal reorganization. We conclude that prolonged exposure of ECs to rapamycin increases p27(Kip1) and in turn inhibits RhoA activation, blocking cell migration and differentiation. These data elucidate the molecular mechanism underlying regulation of p27(Kip1) protein and cell migration by rapamycin.

Risk Factors for the Development of Hospital-Associated Venous Thromboembolism in Adult Patients Admitted to a Children's Hospital.

BACKGROUND AND OBJECTIVES: Hospital-associated venous thromboembolism (HA-VTE) is a leading cause of preventable in-hospital mortality in adults. Our objective was to describe HA-VTE and evaluate risk factors for its development in adults admitted to a children's hospital, which has not been previously studied. We also evaluated the performance of commonly used risk assessment tools for HA-VTE. METHODS: A case-control study was performed at a freestanding children's hospital. Cases of HA-VTE in patients ≥18 years old (2013-2017) and age-matched controls were identified. We extracted patient and HA-VTE characteristics and HA-VTE risk factors on the basis of previous literature. Thrombosis risk assessment was performed retrospectively by using established prospective adult tools (Caprini and Padua scores). RESULTS: Thirty-nine cases and 78 controls were identified. Upper extremities were the most common site of thrombosis (62%). Comorbid conditions were common (91.5%), and malignancy was more common among case patients than controls (P = .04). The presence of a central venous catheter (P < .01), longer length of stay (P < .01), ICU admission (P = .005), and previous admission within 30 days (P = .01) were more common among case patients when compared with controls. Median Caprini score was higher for case patients (P < .01), whereas median Padua score was similar between groups (P = .08). CONCLUSIONS: HA-VTE in adults admitted to children's hospitals is an important consideration in a growing high-risk patient population. HA-VTE characteristics in our study were more similar to published data in pediatrics.

Sera from patients with diabetes do not alter the effect of mammalian target of rapamycin inhibition on smooth muscle cell proliferation.

Clinical studies of drug-eluting stents delivering the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (Sirolimus), have demonstrated a reduced efficacy for these devices in patients with diabetes, which suggests that the mTOR pathway may cease to be dominant in mediating the vascular response to injury under diabetic conditions. We hypothesized that changes in serum composition accompanying diabetes may reduce the role of mTOR in mediating the vascular response to injury. We measured the ability of a median dose of rapamycin (10 nM) to inhibit the proliferation of human coronary artery smooth muscle cells (huCASMCs) stimulated with serum obtained from donors with diabetes (n = 14) and without diabetes (n = 16). In an additional analysis, we compared the effects of rapamycin on huCASMCs stimulated with the serum of donors with metabolic syndrome (n = 15) versus those without (n = 7). There was no difference in the effect of rapamycin on huCASMC proliferation after stimulation with serum from either donors with diabetes or donors with metabolic syndrome compared with the respective controls. We conclude that the changes in the serum composition common to diabetes and metabolic syndrome are insufficient to diminish the role of mTOR in the progression of cardiovascular disease.

Upregulation of miR-221 and -222 in response to increased extracellular signal-regulated kinases 1/2 activity exacerbates neointimal hyperplasia in diabetes mellitus.

BACKGROUND AND AIMS: Diabetes is associated with accelerated arterial intimal thickening that contributes to the increased cardiovascular disease seen in this population. In healthy arteries, intimal thickening is inhibited by elevated levels of the cyclin-dependent kinase inhibitor, p27Kip1, and intimal thickening is promoted by activation of the mammalian Target of Rapamycin to promote degradation of p27Kip1 protein. Recently, we reported that two microRNAs, miR-221 and -222, which promote intimal thickening via down-regulation of mRNA encoding p27Kip1, are elevated in the arteries of diabetic patients. To determine if these miRNAs are critical to the increased intimal thickening under diabetic conditions, we examined the regulation of p27Kip1in a mouse model of diabetes. METHODS: Comparisons of p27Kip1 signaling in NONcNZO10 mice fed a diabetogenic versus control diet were performed using immunochemistry and real-time PCR. RESULTS: Vascular smooth muscle cells and arteries of diabetic mice exhibited decreased levels of p27Kip1 that derived from destabilization of p27Kip1 mRNA in an extracellular signal response kinase-1/2 (ERK-1/2) dependent manner. The activity of ERK-1/2 is increased in the arteries of diabetic mice and promotes an increase in miR-221 and -222. Inhibition of miR-221 and -222 restores normal levels of p27Kip1 mRNA and protein in the arteries of diabetic mice and reduces intimal thickening following wire injury. CONCLUSIONS: These data suggest diabetes is accompanied by increases in arterial miR-221 and -222 expression that promotes intimal thickening. Inhibition of the increased miR-221 and -222 may be efficacious in the prevention of the cardiovascular complications of diabetes.

Elevated serum bone morphogenetic protein 4 in patients with chronic kidney disease and coronary artery disease.

Chronic kidney disease (CKD) is associated with increased coronary artery disease (CAD) and coronary artery calcification. We hypothesized that the osteogenic factor, bone morphogenetic protein-4 (sBMP-4), is elevated in subjects with both CKD and CAD. Serum was collected from 79 subjects undergoing diagnostic angiography and stratified according to CAD and CKD status. Subjects with both CAD and CKD had significantly elevated sBMP-4 compared to those with only one or no disease. sBMP-4 continued to be associated with the presence of both diseases after adjustment for other risk factors. To determine if sBMP-4 is associated with coronary artery calcification, we compared coronary artery calcium scores (CAC) to sBMP-4 in 22 subjects. A positive correlation between CAC and sBMP-4 was seen. In conclusion, sBMP-4 is elevated in patients with both CAD and CKD and positively correlates with CAC, suggesting a role for sBMP-4 in the increased CAD seen in CKD patients.

Elevation of miR-221 and -222 in the internal mammary arteries of diabetic subjects and normalization with metformin.

Diabetes is a major risk factor for cardiovascular disease and is associated with increased intimal thickening and accelerated vascular smooth muscle cell (VSMC) proliferation. We measured the expression of two microRNAs that promote intimal thickening, miR-221/222, and mRNA encoding a downstream target, p27(Kip1), in internal mammary artery (IMA) segments collected from 37 subjects undergoing coronary artery bypass grafting. The segments were stratified into three groups: non-diabetic subjects (ND), diabetic subjects not on metformin (DMMet-), and diabetic subjects on metformin (DMMet+). The DMMet- group exhibited a significant increase in miR-221/222 and decrease in p27(Kip1) mRNA compared to both the ND and DMMet+ groups. miR-221/222 levels inversely correlated with metformin dose. VSMCs isolated from the IMAs of the DMMet- group proliferate at a faster rate than those of the ND and DMMet+ groups. Further studies into the importance of miR-221/222 in the increased intimal thickening observed in diabetic subjects is warranted.

Loss of canonical insulin signaling accelerates vascular smooth muscle cell proliferation and migration through changes in p27Kip1 regulation.

Insulin resistance is associated with an accelerated rate of atherosclerosis. Vascular smooth muscle cell (VSMC) migration and proliferation are important components of atherosclerosis. To elucidate the effects of the loss of normal insulin receptor (IR) signaling on VSMC function, we compared the proliferation and migration of murine VSMCs lacking the IR (L2-VSMCs) with wild type (WT-VSMCs). We also examined changes in the response of L2-VSMCs to insulin stimulation and to inhibition of the mammalian target of rapamycin (mTOR), a kinase critical in VSMC proliferation and migration. The L2-VSMCs exhibit greater proliferation and migration rates compared with WT-VSMCs. L2-VSMCs also exhibit a resistance to the effects of rapamycin, an mTOR inhibitor, on proliferation, migration, and cell cycle progression. The resistance to mTOR inhibition is coupled with a loss of effect on the cyclin-dependent kinase inhibitor p27(Kip1), an inhibitor of cell cycle progression and VSMC migration. In response to stimulation with physiological insulin, the L2-VSMCs exhibit a loss of Akt phosphorylation and a significantly increased activation of the ERK-1/2 compared with WT-VSMCs. Insulin stimulation also decreased p27(Kip1) mRNA in L2-VSMCs but not in WT-VSMCs. The effect of insulin on p27(Kip1) mRNA was blocked by pretreatment with an ERK-1/2 pathway inhibitor. We conclude that loss of canonical insulin signaling results in increased ERK-1/2 activation in response to physiological insulin that decreases p27(Kip1) mRNA. These data demonstrate a potential mechanism where changes in IR signaling could lead to a decrease in p27(Kip1), accelerating VSMC proliferation and migration.

Isolation of endothelial cells and vascular smooth muscle cells from internal mammary artery tissue.

Analyses of vascular smooth muscle cell and endothelial cell function through tissue culture techniques are often employed to investigate the underlying mechanisms regulating cardiovascular disease. As diseases such as diabetes mellitus and chronic kidney disease increase a patient's risk of cardiovascular disease, the development of methods for examining the effects of these diseases on vascular smooth muscle cells and endothelial cells is needed. Commercial sources of endothelial cells and vascular smooth muscle cells generally provide minimal donor information and are in limited supply. This study was designed to determine if vascular smooth muscle cells and endothelial cells could be isolated from human internal mammary arteries obtained from donors undergoing coronary artery bypass graft surgery. As coronary artery bypass graft surgery is a commonly performed procedure, this method would provide a new source for these cells that when combined with the donor's medical history will greatly enhance our studies of the effects of complicating diseases on vascular biology. Internal mammary artery tissue was obtained from patients undergoing coronary artery bypass graft surgery. Through a simple method employing two separate tissue digestions, vascular smooth muscle cells and endothelial cells were isolated and characterized. The isolated vascular smooth muscle cells and endothelial cells exhibited the expected morphology and were able to be passaged for further analysis. The vascular smooth muscle cells exhibited positive staining for α-smooth muscle actin and the endothelial cells exhibited positive staining for CD31. The overall purity of the isolations was > 95%. This method allows for the isolation of endothelial cells and vascular smooth muscle cells from internal mammary arteries, providing a new tool for investigations into the interplay of vascular diseases and complicating diseases such as diabetes and kidney disease.