Local and systemic responses to SARS-CoV-2 infection in children and adults.

It is not fully understood why COVID-19 is typically milder in children1-3. Here, to examine the differences between children and adults in their response to SARS-CoV-2 infection, we analysed paediatric and adult patients with COVID-19 as well as healthy control individuals (total n = 93) using single-cell multi-omic profiling of matched nasal, tracheal, bronchial and blood samples. In the airways of healthy paediatric individuals, we observed cells that were already in an interferon-activated state, which after SARS-CoV-2 infection was further induced especially in airway immune cells. We postulate that higher paediatric innate interferon responses restrict viral replication and disease progression. The systemic response in children was characterized by increases in naive lymphocytes and a depletion of natural killer cells, whereas, in adults, cytotoxic T cells and interferon-stimulated subpopulations were significantly increased. We provide evidence that dendritic cells initiate interferon signalling in early infection, and identify epithelial cell states associated with COVID-19 and age. Our matching nasal and blood data show a strong interferon response in the airways with the induction of systemic interferon-stimulated populations, which were substantially reduced in paediatric patients. Together, we provide several mechanisms that explain the milder clinical syndrome observed in children.

Update on Cardiovascular Implantable Electronic Device Infections and Their Prevention, Diagnosis, and Management: A Scientific Statement From the American Heart Association: Endorsed by the International Society for Cardiovascular Infectious Diseases.

The American Heart Association sponsored the first iteration of a scientific statement that addressed all aspects of cardiovascular implantable electronic device infection in 2010. Major advances in the prevention, diagnosis, and management of these infections have occurred since then, necessitating a scientific statement update. An 11-member writing group was identified and included recognized experts in cardiology and infectious diseases, with a career focus on cardiovascular infections. The group initially met in October 2022 to develop a scientific statement that was drafted with front-line clinicians in mind and focused on providing updated clinical information to enhance outcomes of patients with cardiovascular implantable electronic device infection. The current scientific statement highlights recent advances in prevention, diagnosis, and management, and how they may be incorporated in the complex care of patients with cardiovascular implantable electronic device infection.

Long-term Risk of Serious Infections and Mortality Among Patients Surviving Drug Use-Associated Infective Endocarditis.

Among a statewide cohort of 1874 patients surviving hospitalization for drug use-associated endocarditis during 2017-2020, the 3-year risk of death or future hospitalization was 38% (16% for death before later infection, 14% for recurrent endocarditis, 14% for soft tissue, 9% for bacteremia, 5% for bone/joint, and 4% for spinal infections).

Infective Endocarditis After Transcatheter Versus Surgical Aortic Valve Replacement.

BACKGROUND: Scarce data are available comparing infective endocarditis (IE) following surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). This study aimed to compare the clinical presentation, microbiological profile, management, and outcomes of IE after SAVR versus TAVR. METHODS: Data were collected from the "Infectious Endocarditis after TAVR International" (enrollment from 2005 to 2020) and the "International Collaboration on Endocarditis" (enrollment from 2000 to 2012) registries. Only patients with an IE affecting the aortic valve prosthesis were included. A 1:1 paired matching approach was used to compare patients with TAVR and SAVR. RESULTS: A total of 1688 patients were included. Of them, 602 (35.7%) had a surgical bioprosthesis (SB), 666 (39.5%) a mechanical prosthesis, 70 (4.2%) a homograft, and 350 (20.7%) a transcatheter heart valve. In the SAVR versus TAVR matched population, the rate of new moderate or severe aortic regurgitation was higher in the SB group (43.4% vs 13.5%; P < .001), and fewer vegetations were diagnosed in the SB group (62.5% vs 82%; P < .001). Patients with an SB had a higher rate of perivalvular extension (47.9% vs 27%; P < .001) and Staphylococcus aureus was less common in this group (13.4% vs 22%; P = .033). Despite a higher rate of surgery in patients with SB (44.4% vs 27.3%; P < .001), 1-year mortality was similar (SB: 46.5%; TAVR: 44.8%; log-rank P = .697). CONCLUSIONS: Clinical presentation, type of causative microorganism, and treatment differed between patients with an IE located on SB compared with TAVR. Despite these differences, both groups exhibited high and similar mortality at 1-year follow-up.

18F-FDG PET/CT and radiolabeled leukocyte SPECT/CT imaging for the evaluation of cardiovascular infection in the multimodality context: ASNC Imaging Indications (ASNC I2) Series Expert Consensus Recommendations from ASNC, AATS, ACC, AHA, ASE, EANM, HRS, IDSA, SCCT, SNMMI, and STS.

This document on cardiovascular infection, including infective endocarditis, is the first in the American Society of Nuclear Cardiology Imaging Indications (ASNC I2) series to assess the role of radionuclide imaging in the multimodality context for the evaluation of complex systemic diseases with multi-societal involvement including pertinent disciplines. A rigorous modified Delphi approach was used to determine consensus clinical indications, diagnostic criteria, and an algorithmic approach to diagnosis of cardiovascular infection including infective endocarditis. Cardiovascular infection incidence is increasing and is associated with high morbidity and mortality. Current strategies based on clinical criteria and an initial echocardiographic imaging approach are effective but often insufficient in complicated cardiovascular infection. Radionuclide imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and single photon emission computed tomography/CT leukocyte scintigraphy can enhance the evaluation of suspected cardiovascular infection by increasing diagnostic accuracy, identifying extracardiac involvement, and assessing cardiac implanted device pockets, leads, and all portions of ventricular assist devices. This advanced imaging can aid in key medical and surgical considerations. Consensus diagnostic features include focal/multi-focal or diffuse heterogenous intense 18F-FDG uptake on valvular and prosthetic material, perivalvular areas, device pockets and leads, and ventricular assist device hardware persisting on non-attenuation corrected images. There are numerous clinical indications with a larger role in prosthetic valves, and cardiac devices particularly with possible infective endocarditis or in the setting of prior equivocal or non-diagnostic imaging. Illustrative cases incorporating these consensus recommendations provide additional clarification. Future research is necessary to refine application of these advanced imaging tools for surgical planning, to identify treatment response, and more.

18F-FDG PET/CT and radiolabeled leukocyte SPECT/CT imaging for the evaluation of cardiovascular infection in the multimodality context: ASNC Imaging Indications (ASNC I2) Series Expert Consensus Recommendations from ASNC, AATS, ACC, AHA, ASE, EANM, HRS, IDSA, SCCT, SNMMI, and STS.

This document on cardiovascular infection, including infective endocarditis, is the first in the American Society of Nuclear Cardiology Imaging Indications (ASNC I2) series to assess the role of radionuclide imaging in the multimodality context for the evaluation of complex systemic diseases with multi-societal involvement including pertinent disciplines. A rigorous modified Delphi approach was used to determine consensus clinical indications, diagnostic criteria, and an algorithmic approach to diagnosis of cardiovascular infection including infective endocarditis. Cardiovascular infection incidence is increasing and is associated with high morbidity and mortality. Current strategies based on clinical criteria and an initial echocardiographic imaging approach are effective but often insufficient in complicated cardiovascular infection. Radionuclide imaging with 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (CT) and single photon emission computed tomography/CT leukocyte scintigraphy can enhance the evaluation of suspected cardiovascular infection by increasing diagnostic accuracy, identifying extracardiac involvement, and assessing cardiac implanted device pockets, leads, and all portions of ventricular assist devices. This advanced imaging can aid in key medical and surgical considerations. Consensus diagnostic features include focal/multi-focal or diffuse heterogenous intense 18F-FDG uptake on valvular and prosthetic material, perivalvular areas, device pockets and leads, and ventricular assist device hardware persisting on non-attenuation corrected images. There are numerous clinical indications with a larger role in prosthetic valves, and cardiac devices particularly with possible infective endocarditis or in the setting of prior equivocal or non-diagnostic imaging. Illustrative cases incorporating these consensus recommendations provide additional clarification. Future research is necessary to refine application of these advanced imaging tools for surgical planning, to identify treatment response, and more.

The Impact of Discharge Against Medical Advice on Readmission After Opioid Use Disorder-Associated Infective Endocarditis: a National Cohort Study.

BACKGROUND: Hospitalizations for infective endocarditis (IE) associated with opioid use disorder (O-IE) have increased in the USA and have been linked to high rates of discharge against medical advice (DAMA). DAMA represents a truncation of care for a severe infection, yet patient outcomes after DAMA are unknown. OBJECTIVE: This study aimed to assess readmissions following O-IE and quantify the impact of DAMA on outcomes. DESIGN: A retrospective study of a nationally representative dataset of persons' inpatient discharges in the USA in 2016 PARTICIPANTS: A total of 6018 weighted persons were discharged for O-IE, stratified by DAMA vs. other discharge statuses. Of these, 1331 (22%) were DAMA. MAIN MEASURES: The primary outcome of interest was 30-day readmission rates, stratified by discharge type. We also examined the total number of hospitalizations during the year and estimated the effect of DAMA on readmission. KEY RESULTS: Compared with non-DAMA, those experiencing DAMA were more commonly female, resided in metropolitan areas, lower income, and uninsured. Crude 30-day readmission following DAMA was 50%, compared with 21% for other discharge types. DAMA was strongly associated with readmission in an adjusted logistic regression model (OR 3.72, CI 3.02-4.60). Persons experiencing DAMA more commonly had ≥2 more hospitalizations during the period (31% vs. 18%, p<0.01), and were less frequently readmitted at the same hospital (49% vs 64%, p<0.01). CONCLUSIONS: DAMA occurs in nearly a quarter of patients hospitalized for O-IE and is strongly associated with short-term readmission. Interventions to address the root causes of premature discharges will enhance O-IE care, reduce hospitalizations and improve outcomes.

RNAi screening identifies a mechanosensitive ROCK-JAK2-STAT3 network central to myofibroblast activation.

Myofibroblasts play key roles in wound healing and pathological fibrosis. Here, we used an RNAi screen to characterize myofibroblast regulatory genes, using a high-content imaging approach to quantify α-smooth muscle actin stress fibers in cultured human fibroblasts. Screen hits were validated on physiological compliance hydrogels, and selected hits tested in primary fibroblasts from patients with idiopathic pulmonary fibrosis. Our RNAi screen led to the identification of STAT3 as an essential mediator of myofibroblast activation and function. Strikingly, we found that STAT3 phosphorylation, while responsive to exogenous ligands on both soft and stiff matrices, is innately active on a stiff matrix in a ligand/receptor-independent, but ROCK- and JAK2-dependent fashion. These results demonstrate how a cytokine-inducible signal can become persistently activated by pathological matrix stiffening. Consistent with a pivotal role for this pathway in driving persistent fibrosis, a STAT3 inhibitor attenuated murine pulmonary fibrosis when administered in a therapeutic fashion after bleomycin injury. Our results identify novel genes essential for the myofibroblast phenotype, and point to STAT3 as an important target in pulmonary fibrosis and other fibrotic diseases.

Trends in Drug Use-Associated Infective Endocarditis and Heart Valve Surgery, 2007 to 2017: A Study of Statewide Discharge Data.

Background: Drug use-associated infective endocarditis (DUA-IE) is increasing as a result of the opioid epidemic. Infective endocarditis may require valve surgery, but surgical treatment of DUA-IE has invoked controversy, and the extent of its use is unknown. Objective: To examine hospitalization trends for DUA-IE, the proportion of hospitalizations with surgery, patient characteristics, length of stay, and charges. Design: 10-year analysis of a statewide hospital discharge database. Setting: North Carolina hospitals, 2007 to 2017. Patients: All patients aged 18 years or older hospitalized for IE. Measurements: Annual trends in all IE admissions and in IE hospitalizations with valve surgery, stratified by patients' drug use status. Characteristics of DUA-IE surgical hospitalizations, including patient demographic characteristics, length of stay, disposition, and charges. Results: Of 22 825 IE hospitalizations, 2602 (11%) were for DUA-IE. Valve surgery was performed in 1655 IE hospitalizations (7%), including 285 (17%) for DUA-IE. Annual DUA-IE hospitalizations increased from 0.92 to 10.95 and DUA-IE hospitalizations with surgery from 0.10 to 1.38 per 100 000 persons. In the final year, 42% of IE valve surgeries were performed in patients with DUA-IE. Compared with other surgical patients with IE, those with DUA-IE were younger (median age, 33 vs. 56 years), were more commonly female (47% vs. 33%) and white (89% vs. 63%), and were primarily insured by Medicaid (38%) or uninsured (35%). Hospital stays for DUA-IE were longer (median, 27 vs. 17 days), with higher median charges ($250 994 vs. $198 764). Charges for 282 DUA-IE hospitalizations exceeded $78 million. Limitation: Reliance on administrative data and billing codes. Conclusion: DUA-IE hospitalizations and valve surgeries increased more than 12-fold, and nearly half of all IE valve surgeries were performed in patients with DUA-IE. The swell of patients with DUA-IE is reshaping the scope, type, and financing of health care resources needed to effectively treat IE. Primary Funding Source: National Institutes of Health.

The association between vegetation size and surgical treatment on 6-month mortality in left-sided infective endocarditis.

AIMS: In left-sided infective endocarditis (IE), a large vegetation >10 mm is associated with higher mortality, yet it is unknown whether surgery during the acute phase opposed to medical therapy is associated with improved survival. We assessed the association between surgery and 6-month mortality as related to vegetation size. METHODS AND RESULTS: Patients with definite, left-sided IE (2008-2012) from The International Collaboration on Endocarditis prospective, multinational registry were included. We compared clinical characteristics and 6-month mortality (by Cox regression with inverse propensity of treatment weighting) between patients with vegetation size ≤10 mm vs. >10 mm in maximum length by surgical treatment strategy. A total of 1006 patients with left sided IE were included; 422 with a vegetation size ≤10 mm (median age 66.0 years, 33% women) and 584 (median age 58.4 years, 34% women) patients with a large vegetation >10 mm. Operative risk by STS-IE score was similar between groups. Embolic events occurred in 28.4% vs. 44.3% (P < 0.001), respectively. Patients with a vegetation >10 mm was associated with higher 6-month mortality (25.1% vs. 19.4% for small vegetation, P = 0.035). However, after propensity adjustment, the association with higher mortality persisted only in patients with a large vegetation >10 mm vs. ≤10 mm: hazard ratio (HR) 1.55 (1.27-1.90); but only in patients with large vegetation managed medically [HR 1.86 (1.48-2.34)] rather than surgically [HR 1.01 (0.69-1.49)]. CONCLUSION: Left-sided IE with vegetation size >10 mm was associated with an increased mortality at 6 months in this observational study but was dependent on treatment strategy. For patients with large vegetation undergoing surgical treatment, survival was similar to patients with smaller vegetation size.

Association between the timing of surgery for complicated, left-sided infective endocarditis and survival.

BACKGROUND: In patients with active infective endocarditis (IE), the relationship between timing of surgery and survival is uncertain. The objective was to evaluate clinical characteristics associated with timing of surgery and the association between surgical timing and 6-month survival in complicated, left-sided IE. METHODS: In a prospective, multicenter, observational registry (The International Collaboration on Endocarditis-PLUS, registry from 2008 to 2012), clinical factors associated with timing of surgery during the index hospitalization were determined among 485 adult patients with definite, complicated, left-sided IE who underwent cardiac surgery during their index hospitalization. The relationship between early surgical intervention (<7 days from admission to surgery center) and outcome after surgery was analyzed. The primary end point of the study was 6-month survival. RESULTS: The median time to surgery from admission to surgical center was 7 (interquartile range 2-15) days. Patients who underwent earlier surgery were more likely transferred to the surgical center (74.2% vs 46.4%, P < .001) and had a lower percentage of preexisting heart failure (before IE diagnosis) (6.0% vs 17.3%, P < .001) but higher rate of acute heart failure (53.2% vs 38.4%, P = .001). Variables independently associated with surgery <7 days from admission were patient transfer, acute heart failure, and nonelective surgical status (C-index = 0.84), but predicted operative risk was not. Cox proportional hazards modeling with inverse probability of treatment weighting found that earlier surgery was associated with a trend toward higher 6-month mortality compared with later surgery (hazard ratio = 1.68, 95% CI 0.97-2.96; P = .065), particularly surgery within 2 days of admission or transfer. Mortality was significantly associated with operative risk and complicated IE, including Staphylococcus aureus infection and presence of abscess. CONCLUSIONS: Earlier surgery in IE is strongly associated with acute heart failure and surgical urgency. After adjustment for operative risk and IE complications, earlier surgery <7 days from admission was associated with a trend toward higher 6-month overall mortality compared with surgery later in the index hospitalization.

Spatial and temporal changes in myogenic protein expression by the microenvironment after freeze injury.

Skeletal muscle has the remarkable capability to regenerate itself following injury. Adult myogenic stem cells (MSCs) are responsible for the repair and regeneration, and their activity is controlled by intrinsic and extrinsic factors. The aim of this study was to examine and compare the expression levels of Pax3, Pax7, MRF and p38 proteins during the course of regeneration and in different areas of the focal freeze-lesion damaged adult rat TA muscle. Using the focal freeze injury model, immunohistochemistry, laser-capture micro-dissection and Western blot analysis were performed. The results show that (1) in the severely damaged area, the focal freeze-lesion injury significantly activated Pax7 and myogenin expression within 7 days and down-regulated Pax3, MyoD and Myf-5 within 1 or 3 days, and (2) the level of the p38 protein was strongly and transiently up-regulated in the whole muscle on day 7 following injury, whereas the level of the pp38 protein was down-regulated within 3 days in the severely damaged and non-damaged areas. These findings indicate that the temporal (e.g. the time course of regeneration) and spatial (e.g. three zones created by the focal freeze-lesion) cues in a regenerating muscle have a significant impact on the activity of the adult MSCs.

Management Considerations in Infective Endocarditis: A Review.

Importance: Infective endocarditis occurs in approximately 15 of 100 000 people in the United States and has increased in incidence. Clinicians must make treatment decisions with respect to prophylaxis, surgical management, specific antibiotics, and the length of treatment in the setting of emerging, sometimes inconclusive clinical research findings. Observations: Community-associated infective endocarditis remains the predominant form of the disease; however, health care accounts for one-third of cases in high-income countries. As medical interventions are increasingly performed on older patients, the disease incidence from cardiac implanted electronic devices is also increasing. In addition, younger patients involved with intravenous drug use has increased in the past decade and with it the proportion of US hospitalization has increased to more than 10%. These epidemiological factors have led to Staphylococcus aureus being the most common cause in high-income countries, accounting for up to 40% of cases. The mainstays of diagnosis are still echocardiography and blood cultures. Adjunctive imaging such as cardiac computed tomographic and nuclear imaging can improve the sensitivity for diagnosis when echocardiography is not conclusive. Serological studies, histopathology, and polymerase chain reaction assays have distinct roles in the diagnosis of infective endocarditis when blood culture have tested negative with the highest yield obtained from serological studies. Increasing antibiotic resistance, particularly to S aureus, has led to a need for different antibiotic treatment options such as newer antibiotics and combination therapy regimens. Surgery can confer a survival benefit to patients with major complications; however, the decision to pursue surgery must balance the risks and benefits of operations in these frequently high-risk patients. Conclusions and Relevance: The epidemiology and management of infective endocarditis are continually changing. Guidelines provide specific recommendations about management; however, careful attention to individual patient characteristics, pathogen, and risk of sequela must be considered when making therapeutic decisions.

Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial.

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]). Conclusions and Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration: ClinicalTrials.gov Identifier: NCT01191840.

Association between surgical indications, operative risk, and clinical outcome in infective endocarditis: a prospective study from the International Collaboration on Endocarditis.

BACKGROUND: Use of surgery for the treatment of infective endocarditis (IE) as related to surgical indications and operative risk for mortality has not been well defined. METHODS AND RESULTS: The International Collaboration on Endocarditis-PLUS (ICE-PLUS) is a prospective cohort of consecutively enrolled patients with definite IE from 29 centers in 16 countries. We included patients from ICE-PLUS with definite left-sided, non-cardiac device-related IE who were enrolled between September 1, 2008, and December 31, 2012. A total of 1296 patients with left-sided IE were included. Surgical treatment was performed in 57% of the overall cohort and in 76% of patients with a surgical indication. Reasons for nonsurgical treatment included poor prognosis (33.7%), hemodynamic instability (19.8%), death before surgery (23.3%), stroke (22.7%), and sepsis (21%). Among patients with a surgical indication, surgical treatment was independently associated with the presence of severe aortic regurgitation, abscess, embolization before surgical treatment, and transfer from an outside hospital. Variables associated with nonsurgical treatment were a history of moderate/severe liver disease, stroke before surgical decision, and Staphyloccus aureus etiology. The integration of surgical indication, Society of Thoracic Surgeons IE score, and use of surgery was associated with 6-month survival in IE. CONCLUSIONS: Surgical decision making in IE is largely consistent with established guidelines, although nearly one quarter of patients with surgical indications do not undergo surgery. Operative risk assessment by Society of Thoracic Surgeons IE score provides prognostic information for survival beyond the operative period. S aureus IE was significantly associated with nonsurgical management.

Enteral Feeding with Human Milk Decreases Time to Discharge in Infants following Gastroschisis Repair.

OBJECTIVE: To assess the effect of enteral feeding with human milk on the time from initiation of feeds to discharge after gastroschisis repair through review of a multi-institutional database. STUDY DESIGN: Infants who underwent gastroschisis repair between 1997 and 2012 with data recorded in the Pediatrix Medical Group Clinical Data Warehouse were categorized into 4 groups based on the percentage of days fed human milk out of the number of days fed enterally. Cox proportional hazards regression modeling was performed to determine the adjusted effect of human milk on the time from initiation of feeds to discharge. RESULTS: Among 3082 infants, 659 (21%) were fed human milk on 0% of enteral feeding days, 766 (25%) were fed human milk on 1%-50% of enteral feeding days, 725 (24%) were fed human milk on 51%-99% of enteral feeding days, and 932 (30%) were fed human milk on 100% of enteral feeding days. Following adjustment, being fed human milk on 0% of enteral feeding days was associated with a significantly increased time to discharge compared with being fed human milk on 100% of enteral feeding days (hazard ratio [HR] for discharge per day, 0.46; 95% CI, 0.40-0.52). The same was found for infants fed human milk on 1%-50% of enteral feeding days (HR, 0.37; 95% CI, 0.32-0.41) and for infants fed human milk on 51%-99% of enteral feeding days (HR, 0.51; 95% CI, 0.46-0.57). CONCLUSION: The use of human milk for enteral feeding of infants following repair of gastroschisis significantly reduces the time to discharge from initiation of feeds.

Vitamin D attenuates cytokine-induced remodeling in human fetal airway smooth muscle cells.

Asthma in the pediatric population remains a significant contributor to morbidity and increasing healthcare costs. Vitamin D3 insufficiency and deficiency have been associated with development of asthma. Recent studies in models of adult airway diseases suggest that the bioactive Vitamin D3 metabolite, calcitriol (1,25-dihydroxyvitamin D3 ; 1,25(OH)2 D3 ), modulates responses to inflammation; however, this concept has not been explored in developing airways in the context of pediatric asthma. We used human fetal airway smooth muscle (ASM) cells as a model of the early postnatal airway to explore how calcitriol modulates remodeling induced by pro-inflammatory cytokines. Cells were pre-treated with calcitriol and then exposed to TNFα or TGFß for up to 72 h. Matrix metalloproteinase (MMP) activity, production of extracellular matrix (ECM), and cell proliferation were assessed. Calcitriol attenuated TNFα enhancement of MMP-9 expression and activity. Additionally, calcitriol attenuated TNFα and TGFß-induced collagen III expression and deposition, and separately, inhibited proliferation of fetal ASM cells induced by either inflammatory mediator. Analysis of signaling pathways suggested that calcitriol effects in fetal ASM involve ERK signaling, but not other major inflammatory pathways. Overall, our data demonstrate that calcitriol can blunt multiple effects of TNFα and TGFß in developing airway, and point to a potentially novel approach to alleviating structural changes in inflammatory airway diseases of childhood.

Impact of early valve surgery on outcome of Staphylococcus aureus prosthetic valve infective endocarditis: analysis in the International Collaboration of Endocarditis-Prospective Cohort Study.

BACKGROUND: The impact of early valve surgery (EVS) on the outcome of Staphylococcus aureus (SA) prosthetic valve infective endocarditis (PVIE) is unresolved. The objective of this study was to evaluate the association between EVS, performed within the first 60 days of hospitalization, and outcome of SA PVIE within the International Collaboration on Endocarditis-Prospective Cohort Study. METHODS: Participants were enrolled between June 2000 and December 2006. Cox proportional hazards modeling that included surgery as a time-dependent covariate and propensity adjustment for likelihood to receive cardiac surgery was used to evaluate the impact of EVS and 1-year all-cause mortality on patients with definite left-sided S. aureus PVIE and no history of injection drug use. RESULTS: EVS was performed in 74 of the 168 (44.3%) patients. One-year mortality was significantly higher among patients with S. aureus PVIE than in patients with non-S. aureus PVIE (48.2% vs 32.9%; P = .003). Staphylococcus aureus PVIE patients who underwent EVS had a significantly lower 1-year mortality rate (33.8% vs 59.1%; P = .001). In multivariate, propensity-adjusted models, EVS was not associated with 1-year mortality (risk ratio, 0.67 [95% confidence interval, .39-1.15]; P = .15). CONCLUSIONS: In this prospective, multinational cohort of patients with S. aureus PVIE, EVS was not associated with reduced 1-year mortality. The decision to pursue EVS should be individualized for each patient, based upon infection-specific characteristics rather than solely upon the microbiology of the infection causing PVIE.