Defining necrotizing enterocolitis: current difficulties and future opportunities.

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in hospitalized infants. First classified through Bell staging in 1978, a number of additional definitions of NEC have been proposed in the subsequent decades. In this review, we summarize eight current definitions of NEC, and explore similarities and differences in clinical signs and radiographic features included within these definitions, as well as their limitations. We highlight the importance of a global consensus on defining NEC to improve NEC research and outcomes, incorporating input from participants at an international NEC conference. We also highlight the important role of patient-families in helping to redefine NEC.

Human milk fortification: the clinician and parent perspectives.

This study reports on the human milk fortification session at the 2019 NEC Society Symposium, which included clinicians and parents discussing the evidence comparing fortification options such as efficacy, safety, cost effectiveness, and the need for parents to be informed about fortifier choice. With the current literature available and the varying standard of care practices for human milk fortification, further studies are needed to determine the most complete diet for preterm infants. The optimal diet would not only provide key nutrients and energy for growth and development, but also improve short- and long-term outcomes. Parents, as advocates and providers for their infant, should be informed, educated, and included in the discussion and decisions regarding fortification of human milk for their infant.

Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx.

Aldosterone contributes to end-organ damage in heart failure and chronic kidney disease. Mineralocorticoid-receptor inhibitors limit activation of the receptor by aldosterone and slow disease progression, but side effects, including hyperkalemia, limit their clinical use. Damage to the endothelial glycocalyx (a luminal biopolymer layer) has been implicated in the pathogenesis of endothelial dysfunction and albuminuria, but to date no one has investigated whether the glomerular endothelial glycocalyx is affected by aldosterone. In vitro, human glomerular endothelial cells exposed to 0.1 nM aldosterone and 145 mMol NaCl exhibited reduced cell surface glycocalyx components (heparan sulfate and syndecan-4) and disrupted shear sensing consistent with damage of the glycocalyx. In vivo, administration of 0.6 µg/g/d of aldosterone (subcutaneous minipump) and 1% NaCl drinking water increased glomerular matrix metalloproteinase 2 activity, reduced syndecan 4 expression, and caused albuminuria. Intravital multiphoton imaging confirmed that aldosterone caused damage of the glomerular endothelial glycocalyx and increased the glomerular sieving coefficient for albumin. Targeting matrix metalloproteinases 2 and 9 with a specific gelatinase inhibitor preserved the glycocalyx, blocked the rise in glomerular sieving coefficient, and prevented albuminuria. Together these data suggest that preservation of the glomerular endothelial glycocalyx may represent a novel strategy for limiting the pathological effects of aldosterone.

Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy.

Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF-A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy.

Clinical outcomes in real-world patients with acute myocardial infarction receiving XIENCE V® everolimus-eluting stents: one-year results from the XIENCE V USA study.

OBJECTIVES: The objective of this analysis was to evaluate the safety and effectiveness of XIENCE V in acute myocardial infarction (AMI). BACKGROUND: The XIENCE V(®) Everolimus-eluting coronary stent was superior to the TAXUS(®) paclitaxel-eluting stent in angiographic and clinical outcomes in the SPIRIT II, III, and IV randomized controlled trials, but patients with AMI were excluded. METHODS: XIENCE V USA is a large, prospective, multicenter, real-world single-arm postmarket surveillance trial. Consecutive patients undergoing PCI with XIENCE V were enrolled. For this analysis, clinical outcomes in 673 patients presenting with AMI (STEMI, n = 125) were as compared to patients without AMI (n = 3528) at 1 year. RESULTS: At 1 year, ARC-defined stent thrombosis (ST) rates were 1.08% in AMI vs. 0.85% in the non-AMI group (P = 0.4987). The late ST (30 days-1 year) rates were 0.31% vs. 0.47% (AMI vs. non-AMI, P = 0.7551). Rates of target lesion revascularization (TLR) were 4.1% vs. 4.6% (P = 0.6104), and rates of target lesion failure (TLF) were 9.1% vs. 8.5%, (P = 0.5964). With the historical WHO definition of MI, 1 year TLF rates were 7.0% vs. 6.7% (P = 0.8001). Improvements in quality of life, angina frequency, angina stability, and physical limitations occurred at 6 months (each P < 0.0001) and were sustained at 1 year in both groups. There were no significant differences in clinical outcomes between STEMI and non-STEMI patients. CONCLUSIONS: At 1 year, AMI patients treated with XIENCE V had low rates of ST, TLR, and TLF, similar to non-AMI patients. Marked improvements in patients' health status in this subgroup were also demonstrated.

Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction.

Patients with albuminuria and CKD frequently have vascular dysfunction but the underlying mechanisms remain unclear. Because the endothelial surface layer, a meshwork of surface-bound and loosely adherent glycosaminoglycans and proteoglycans, modulates vascular function, its loss could contribute to both renal and systemic vascular dysfunction in proteinuric CKD. Using Munich-Wistar-Fromter (MWF) rats as a model of spontaneous albuminuric CKD, multiphoton fluorescence imaging and single-vessel physiology measurements revealed that old MWF rats exhibited widespread loss of the endothelial surface layer in parallel with defects in microvascular permeability to both water and albumin, in both continuous mesenteric microvessels and fenestrated glomerular microvessels. In contrast to young MWF rats, enzymatic disruption of the endothelial surface layer in old MWF rats resulted in neither additional loss of the layer nor additional changes in permeability. Intravenous injection of wheat germ agglutinin lectin and its adsorption onto the endothelial surface layer significantly improved glomerular albumin permeability. Taken together, these results suggest that widespread loss of the endothelial surface layer links albuminuric kidney disease with systemic vascular dysfunction, providing a potential therapeutic target for proteinuric kidney disease.

Mineralocorticoid receptor antagonism in diabetes reduces albuminuria by preserving the glomerular endothelial glycocalyx.

The glomerular endothelial glycocalyx (GEnGlx) forms the first part of the glomerular filtration barrier. Previously, we showed that mineralocorticoid receptor (MR) activation caused GEnGlx damage and albuminuria. In this study, we investigated whether MR antagonism could limit albuminuria in diabetes and studied the site of action. Streptozotocin-induced diabetic Wistar rats developed albuminuria, increased glomerular albumin permeability (Ps'alb), and increased glomerular matrix metalloproteinase (MMP) activity with corresponding GEnGlx loss. MR antagonism prevented albuminuria progression, restored Ps'alb, preserved GEnGlx, and reduced MMP activity. Enzymatic degradation of the GEnGlx negated the benefits of MR antagonism, confirming their dependence on GEnGlx integrity. Exposing human glomerular endothelial cells (GEnC) to diabetic conditions in vitro increased MMPs and caused glycocalyx damage. Amelioration of these effects confirmed a direct effect of MR antagonism on GEnC. To confirm relevance to human disease, we used a potentially novel confocal imaging method to show loss of GEnGlx in renal biopsy specimens from patients with diabetic nephropathy (DN). In addition, patients with DN randomized to receive an MR antagonist had reduced urinary MMP2 activity and albuminuria compared with placebo and baseline levels. Taken together, our work suggests that MR antagonists reduce MMP activity and thereby preserve GEnGlx, resulting in reduced glomerular permeability and albuminuria in diabetes.

Overexpression of VEGF165b in podocytes reduces glomerular permeability.

The observation that therapeutic agents targeting vascular endothelial growth factor-A (VEGF-A) associate with renal toxicity suggests that VEGF plays a role in the maintenance of the glomerular filtration barrier. Alternative mRNA splicing produces the VEGF(xxx)b family, which consists of antiangiogenic peptides that reduce permeability and inhibit tumor growth; the contribution of these peptides to normal glomerular function is unknown. Here, we established and characterized heterozygous and homozygous transgenic mice that overexpress VEGF(165)b specifically in podocytes. We confirmed excess production of glomerular VEGF(165)b by reverse transcriptase-PCR, immunohistochemistry, and ELISA in both heterozygous and homozygous animals. Macroscopically, the mice seemed normal up to 18 months of age, unlike the phenotype of transgenic podocyte-specific VEGF(164)-overexpressing mice. Animals overexpressing VEGF(165)b, however, had a significantly reduced normalized glomerular ultrafiltration fraction with accompanying changes in ultrastructure of the glomerular filtration barrier on the vascular side of the glomerular basement membrane. These data highlight the contrasting properties of VEGF splice variants and their impact on glomerular function and phenotype.

Effects of a fixed-dose ACE inhibitor-diuretic combination on ambulatory blood pressure and arterial properties in isolated systolic hypertension.

The ideal therapy for patients with isolated systolic hypertension remains unclear; diuretics, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors are all used in clinical practice. The aim of this study was to determine whether a fixed-dose ACE inhibitor/diuretic combination would reduce ambulatory blood pressures (BP) and arterial stiffness in isolated systolic hypertension more than antihypertensive monotherapy. In this randomized, double-blind study, 8 weeks of fosinopril/hydrochlorothiazide combination (10/12.5 mg titrated up to 20/12.5 mg) was compared with the calcium channel blocker (amlodipine, 5 mg titrated up to 10 mg) and diuretic (indapamide, 2.5 mg) monotherapy in 28 patients with isolated systolic hypertension. Each patient received all 3 therapies. Assessments included 24-hour ambulatory BP, clinic BP, and applanation tonometry-derived augmentation index. At 8 weeks, the fall in average 24-hour systolic BP and night time systolic BP were significantly greater in the fosinopril-hydrochlorothiazide group, compared to amlodipine and indapamide. The decrease in augmentation index and central aortic systolic BP was also greater in the fosinopril-hydrochlorothiazide group, compared to either amlodipine or indapamide. There was no difference between therapies in decrease in clinic systolic or diastolic BP, or diastolic ABP (average 24-h, diurnal, or nocturnal). Compared with either calcium channel blocker or diuretic therapy, a fixed-dose ACE inhibitor-diuretic combination induces greater reductions in systolic ABP, particularly at night, favorable effects that may be related to a decrease in the intensity of or delay in arterial wave reflections. ACE inhibitor-diuretic combination therapy is a useful approach to cardiovascular risk reduction in isolated systolic hypertension.

Boston bombings: response to disaster.

Disasters disrupt everyone's lives, and they can disrupt the flow and function of an OR as well as affect personnel on a professional and personal level even though perioperative departments and their personnel are used to caring for trauma patients and coping with surprises. The Boston Marathon bombing was a new experience for personnel at Massachusetts General Hospital, Boston. This article discusses the incidents surrounding the bombing and how personnel at this hospital met the challenge of caring for patients and the changes we made after the experience to be better prepared in the event a response to a similar incident is needed.

Risk factors for coronary drug-eluting stent thrombosis: influence of procedural, patient, lesion, and stent related factors and dual antiplatelet therapy.

The complication of stent thrombosis (ST) emerged at a rate of 0.5% annually for first-generation drug-eluting stents (DES), often presenting as death or myocardial infarction. Procedural factors such as stent underexpansion and malapposition are risk factors for ST in patients. The type of lesion being treated and lesion morphology also influence healing after treatment with DES and can contribute to ST. Second-generation DES such as the XIENCE V everolimus-eluting stent differ from the first-generation stents with respect to antiproliferative agents, coating technologies, and stent frame. Improvements in stent structure have resulted in a more complete endothelialization, thereby decreasing the incidence of ST. Bioresorbable scaffolds show promise for restoring vasomotor function and minimizing rates of very late ST. Post-PCI treatment with aspirin and clopidogrel for a year is currently the standard of care for DES, but high-risk patients may benefit from more potent antiplatelet agents. The optimal duration of DAPT for DES is currently unclear and will be addressed in large-scale randomized clinical trials.

Impact of age on clinical outcomes after everolimus-eluting and paclitaxel-eluting stent implantation: pooled analysis from the SPIRIT III and SPIRIT IV clinical trials.

AIMS: The impact of age on outcomes following everolimus-eluting stent (EES) or paclitaxel-eluting stent (PES) implantation was evaluated in a patient-level pooled analysis of the SPIRIT III (n=1,002) and SPIRIT IV (n=3,687) trials. METHODS AND RESULTS: Clinical outcomes with EES compared to PES in elderly (≥ 65 years, n=2,071) and younger (<65 years, n=2,617) patients were evaluated at one year. At one year, elderly patients treated with EES rather than PES showed a significant reduction in target lesion failure (TLF) (3.9% EES vs. 6.8% PES, p=0.006), major adverse cardiac events (MACE) (4.0% EES vs. 7.1% PES, p=0.005), and ischaemia-driven target lesion revascularisation (ID-TLR) (2.0% EES vs. 4.0% PES, p=0.01). Younger patients treated with EES rather than PES also had significantly reduced one-year rates of TLF (4.9% EES vs. 7.9% PES, p=0.003), MACE (5.0% EES vs. 8.0% PES, p=0.004), target vessel myocardial infarction (MI) (2.0% EES vs. 3.4% PES, p=0.04), ID-TLR (3.3% EES vs. 5.5% PES, p=0.01) and stent thrombosis (0.5% EES vs. 1.6% PES, p=0.01). CONCLUSIONS: In a pooled analysis from the SPIRIT III and IV trials, EES was safer and more effective than PES in both younger and older cohorts as evidenced by lower rates of TLR, TLF and MACE.

Comparison of everolimus-eluting and paclitaxel-eluting coronary stents in patients undergoing multilesion and multivessel intervention: the SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) and SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) randomized trials.

OBJECTIVES: We evaluated outcomes following XIENCE V everolimus-eluting stent (EES) compared with the Taxus Express(2) paclitaxel-eluting stent (PES) in patients undergoing multilesion and multivessel intervention. BACKGROUND: The optimal revascularization strategy for patients with multivessel disease is unknown. METHODS: The SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) (n = 1,002) and SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) (n = 3,690) trials enrolled patients with de novo lesions ≤ 28 mm in length and reference vessel diameter of 2.5 to 3.75 mm. The SPIRIT III trial enrolled patients with a single lesion in 1 or 2 coronary arteries, and the SPIRIT IV trial enrolled patients with up to 2 lesions in 3 different vessels (maximum 2 lesions per vessel). In both trials, patients were randomized 2:1 to EES vs. PES. Clinical outcomes to 1 year were analyzed in patients with single (n = 3,823) versus multiple (n = 765) treated vessels, and in those with single (n = 3,536) versus multiple (n = 1,052) treated lesions. RESULTS: Among patients with multivessel disease, EES compared with PES resulted in reduced rates of target vessel myocardial infarction (2.2% vs. 6.1%, p = 0.007) and ischemia-driven target lesion revascularization (4.2% vs. 8.0%, p = 0.04). Among patients undergoing multilesion stenting, EES compared with PES resulted in reduced rates of target vessel myocardial infarction (2.1% vs. 5.4%, p = 0.008) and ischemia-driven target lesion revascularization (3.7% vs. 7.4%, p = 0.01). The absolute benefits of EES versus PES in patients undergoing multivessel or multilesion intervention were greater than in those undergoing single-lesion, single-vessel intervention. CONCLUSIONS: The EES compared with PES provided significant improvements in clinical safety and efficacy outcomes. The absolute benefit provided by EES versus PES appears to be proportional to the complexity of coronary disease.