The natural history of asymptomatic central venous catheter-related thrombosis in critically ill children.

Asymptomatic central venous catheter (CVC)-related thrombosis in children varies in incidence from 5% to 69%. The rate of acute and long-term complications, such as postthrombotic syndrome (PTS), from asymptomatic CVC-related thrombosis is unknown. This article reports the outcomes of a prospective study of 189 children in pediatric intensive care that aimed to determine the frequency of asymptomatic CVC-related thrombosis during hospital admission, and the incidence of residual CVC-related thrombosis and clinically significant PTS 2 years later. Risk factors associated with CVC-related thrombosis were also identified. This study is distinct from previous work as children identified to have asymptomatic CVC-related thrombosis were not treated (clinical team kept blinded) and the entire cohort was followed for 2 years to determine the natural history of asymptomatic thrombosis. Ultrasounds of 146 children determined a 21.9% incidence of acute CVC-related thrombosis. Two children were symptomatic. No radiological thrombosis extension or clinical embolization occurred in the 126 children assessed at follow-up. Using 2 recognized PTS scales, clinically significant PTS was reported in 2 children (1 symptomatic, 1 asymptomatic CVC-related thrombosis), however, neither had functional impairment. Cardiac arrest was a risk factor for CVC-related thrombosis during admission and femoral CVC placement was predictive of residual thrombosis 2 years later. This study challenges the notion that critically ill children with asymptomatic CVC-related thrombosis require anticoagulant treatment, as the results demonstrate that the incidence of acute or long-term complications is low. A larger confirmatory study of nontreatment of CVC-related thrombosis in critically ill children is justified.

The clinical utility of fluorodeoxyglucose-positron emission tomography for investigation of fever in immunocompromised children.

AIM: Fever in immunocompromised children presents significant challenges. We aimed to determine the clinical impact of fluorodeoxyglucose-positron emission tomography (FDG-PET) in combination with computed tomography (CT) in children with malignancy or following haematopoietic stem cell transplantation with prolonged or recurrent fever. METHODS: Immunocompromised children who underwent FDG-PET/CT for investigation of prolonged or recurrent fever were identified from hospital databases. The clinical impact of the FDG-PET/CT was considered 'high' if it contributed to any of the following: diagnosis of a new site infection/inflammation, change to antimicrobials or chemotherapy, or additional investigations or specialist consult contributing to final diagnosis. RESULTS: Fourteen patients underwent an FDG-PET/CT for prolonged or recurrent fever. Median age was 11 years and 46% had diagnosis of acute lymphoblastic leukaemia. The median absolute neutrophil count on the day of FDG-PET/CT was 0.47 cells/µL. The clinical impact of FDG-PET/CT was 'high' in 11 (79%) patients, contributing to rationalisation of antimicrobials in three, and cessation of antimicrobials in five. Compared to conventional imaging, FDG PET/CT identified seven additional sites of clinically significant infection/inflammation in seven patients. Of the 10 patients who had a cause of fever identified, FDG-PET/CT contributed to the final diagnosis in six (60%). CONCLUSION: This study has identified potential utility for FDG-PET/CT in immunocompromised children with prolonged or recurrent fever. Further prospective studies are needed to compare FDG-PET/CT versus conventional imaging, to identify the optimal timing of FDG-PET/CT and to study the role of subsequent scans to monitor response to therapy.

International Consensus Statement on the Radiological Screening of Contact Children in the Context of Suspected Child Physical Abuse.

Importance: Physical abuse is a common but preventable cause of long-term childhood morbidity and mortality. Despite the strong association between abuse in an index child and abuse in contact children, there is no guidance outlining how to screen the latter, significantly more vulnerable group, for abusive injuries. Consequently, the radiological assessment of contact children is often omitted, or variably performed, allowing occult injuries to go undetected and increasing the risk of further abuse. Objective: To report an evidence-based and consensus-derived set of best practices for the radiological screening of contact children in the context of suspected child physical abuse. Evidence Review: This consensus statement is supported by a systematic review of the literature and the clinical opinion of an internationally recognized group of 26 experts. The modified Delphi consensus process comprised 3 meetings of the International Consensus Group on Contact Screening in Suspected Child Physical Abuse held between February and June 2021. Findings: Contacts are defined as the asymptomatic siblings, cohabiting children, or children under the same care as an index child with suspected child physical abuse. All contact children should undergo a thorough physical examination and a history elicited prior to imaging. Contact children younger than 12 months should have neuroimaging, the preferred modality for which is magnetic resonance imaging, and skeletal survey. Contact children aged 12 to 24 months should undergo skeletal survey. No routine imaging is indicated in asymptomatic children older than 24 months. Follow-up skeletal survey with limited views should be performed if abnormal or equivocal at presentation. Contacts with positive findings should be investigated as an index child. Conclusions and Relevance: This Special Communication reports consensus recommendations for the radiological screening of contact children in the context of suspected child physical abuse, establishing a recognized baseline for the stringent evaluation of these at-risk children and providing clinicians with a more resilient platform from which to advocate for them.

Justifying referrals for paediatric CT.

• The system of radiation protection assumes a linear dose-response relationship with no threshold for low doses and dose rate exposures. This is based on epidemiological evidence at higher doses. • Hence there is a small theoretical risk of carcinogenesis attributable to low doses of ionising radiation. This risk is associated with any diagnostic imaging procedure involving radiation. • Radiosensitivity declines with age, so children are more susceptible to radiation risks than adults. Females are more radiosensitive than males. • The radiation protection system is based on the assumption that radiation risk is cumulative over a lifetime. • For an individual, a justified, optimised computed tomography (CT) scan will result in more benefit than harm. A doctor must justify the necessity for a CT scan before referring an individual for imaging.

Slow-transit constipation with concurrent upper gastrointestinal dysmotility and its response to transcutaneous electrical stimulation.

PURPOSE: Transcutaneous electrical stimulation (TES) speeds up colonic transit in children with slow-transit constipation (STC). This study examined if concurrent upper gastrointestinal dysmotility (UGD) affected response to TES. METHODS: Radio-nuclear transit studies (NTS) were performed before and after TES treatment of STC as part of a larger randomised controlled trial. UGD was defined as delayed gastric emptying and/or slow small bowel transit. Improvement was defined as increase of ≥1 Geometric Centre (median radiotracer position at each time [small bowel = 1, toilet = 6]). RESULTS: Forty-six subjects completed the trial, 34 had NTS after stimulation (21 M, 8-17 years, mean 11.3 years; symptoms >9 years). Active stimulation increased transit in >50% versus only 25% with sham (p = 0.04). Seventeen children also had UGD. In children with STC and either normal upper GI motility (NUGM) and UGD, NTS improved slightly after 1 month (57 vs. 60%; p = 0.9) and more after 2 months (88 vs. 40%; p = 0.07). However, mean transit rate significantly increased with NUGM, but not UGD (5.0 ± 0.2: 3.6 ± 0.6, p < 0.01). CONCLUSION: Transcutaneous electrical stimulation was beneficial for STC, with response weakly associated with UGD. As measured by NTS, STC children with NUGM responded slightly more, but with significantly greater increased transit compared to those with UGD. Higher numbers are needed to determine if the difference is important.

Ferric iron reductases and their contribution to unicellular ferrous iron uptake.

Iron is a necessary element for nearly all forms of life, and the ability to acquire this trace nutrient has been identified as a key virulence factor for the establishment of infection by unicellular pathogens. In the presence of O2, iron typically exists in the ferric (Fe3+) oxidation state, which is highly unstable in aqueous conditions, necessitating its sequestration into cofactors and/or host proteins to remain soluble. To counter this insolubility, and to compete with host sequestration mechanisms, many unicellular pathogens will secrete low molecular weight, high-affinity Fe3+ chelators known as siderophores. Once acquired, unicellular pathogens must liberate the siderophore-bound Fe3+ in order to assimilate this nutrient into metabolic pathways. While these organisms may hydrolyze the siderophore backbone to release the chelated Fe3+, this approach is energetically costly. Instead, iron may be liberated from the Fe3+-siderophore complex through reduction to Fe2+, which produces a lower-affinity form of iron that is highly soluble. This reduction is performed by a class of enzymes known as ferric reductases. Ferric reductases are broadly-distributed electron-transport proteins that are expressed by numerous infectious organisms and are connected to the virulence of unicellular pathogens. Despite this importance, ferric reductases remain poorly understood. This review provides an overview of our current understanding of unicellular ferric reductases (both soluble and membrane-bound), with an emphasis on the important but underappreciated connection between ferric-reductase mediated Fe3+ reduction and the transport of Fe2+ via ferrous iron transporters.

Pancreatic trauma in children.

PURPOSE: To document the demographics, mechanisms and outcome of traumatic pancreatitis in children at a single large tertiary referral centre in Australia. METHODS: We undertook a 10-year retrospective audit of children admitted to the Royal Children's Hospital, Melbourne, Australia with a hospital coded diagnosis which included pancreatic injury between 1993 and 2002. Data included patient demographics, source of admission, mechanism of injury, pancreatic complications, associated injuries, intensive care unit admission, results of any operative findings, results of any acute computed tomography and/or ultrasound imaging of pancreas, selected laboratory findings and length of stay. RESULTS: We identified two distinct groups of patients in the 91 documented cases of pancreatic trauma (median age 8.0 years, range 0.6-15.8 years; M:F 2.5:1.0): 59 had a history of abdominal trauma and elevated serum lipase but no CT or ultrasound evidence of pancreatic injury (Group A); 32 had a history of abdominal trauma, elevated serum lipase but also had CT scan and/or ultrasound evidence of pancreatic injury (Group B). Patients with "less severe" injury based on normal imaging had a lower initial lipase level [Group A, median 651 U/L (interquartile range 520-1,324) vs. Group B, 1,608 U/L (interquartile range 680-3,526); p = 0.005] and shorter admission time [Group A, 9.0 days (interquartile range 5.5-15.5) vs. Group B, 13.4 days (interquartile range 6.8-23.8); p = 0.04]. There were no differences with respect to mortality (Group A, 13.5% vs. Group B, 12.5%), but patients with evidence of injury on imaging were more likely to have surgical intervention (p = 0.0001). The single most important overall cause of pancreatic trauma was involvement in a motor vehicle accident as a passenger or pedestrian. However, in children with high-grade ductal injury, bicycle handlebar injuries were most common. Associated injuries were common in both groups. CONCLUSION: Significant pancreatic injury can occur in the absence of abnormality on medical imaging. Pancreatic trauma commonly occurs in the context of multiple injuries after motor vehicle accidents in children and bicycle handlebar injuries, especially in boys. Most children can be treated conservatively, with surgical intervention being limited to high-grade ductal injury.

Creatinine-based estimation of glomerular filtration rate in patients with a Fontan circulation.

BACKGROUND: Patients with a Fontan circulation are at risk of renal dysfunction. We analyzed cross-sectional data in pediatric and adult Fontan patients in order to assess the accuracy of commonly used serum creatinine-based methods in estimating glomerular filtration rate (GFR). METHODS: A total of 124 Fontan patients (58 children, 66 adults) were enrolled across three study centers. Measurement of GFR (mGFR) using in vivo 99m Tc-DTPA clearance was performed. Various serum creatinine-based equations were used to calculate estimated GFR (eGFR). RESULTS: Mean mGFR was 108 ± 28 mL/min/1.73 m2 in children and 92 ± 20 mL/min/1.73 m2 in adults. Fourteen children (25%) and 28 adults (45%) had an mGFR <90 mL/min/1.73 m2 . There was no significant correlation between mGFR and eGFR (Schwartz) in children (r = 0.22, P = .1), which substantially overestimated mGFR (bias 50.8, 95%CI: 41.1-60.5 mL/min/1.73 m2 , P < .0001). The Bedside Schwartz equation also performed poorly in the children (r = 0.08, P = .5; bias 5.9, 95%CI: -2.9-14.6 mL/min/1.73 m2 , P < .0001). There was a strong correlation between mGFR and both eGFR (CKD-EPI) and eGFR (MDRD) in adults (r = 0.67, P < .0001 in both cases), however, both methods overestimated mGFR (eGFR(CKD-EPI):bias 23.8, 95%CI: 20-27.6 mL/min/1.73 m2 , P < .0001; eGFR (MDRD):bias 16.1, 95%CI: 11.8-20.4 mL/min/1.73 m2 , P < .0001). None of the children with an mGFR <90 mL/min/1.73 m2 had an eGFR (Schwartz) <90 mL/min/1.73 m2 . Sensitivity and specificity of eGFR (CKD-EPI) and eGFR (MDRD) for mGFR <90 mL/min/1.73 m2 in adults were 25% and 92% and 39% and 100%, respectively. CONCLUSIONS: This study identifies the unreliability of using creatinine-based equations to estimate GFR in children with a Fontan circulation. The accuracy of formulas incorporating cystatin C should be further investigated and may aid noninvasive surveillance of renal function in this population.

Hepatic and renal end-organ damage in the Fontan circulation: A report from the Australian and New Zealand Fontan Registry.

BACKGROUND: Hepatic and renal dysfunction have been observed in survivors of the Fontan procedure, however their incidence and associated factors remain poorly defined. METHODS: A total of 152 participants from a Registry of 1528 patients underwent abdominal ultrasound, transient elastography (FibroScan), serum fibrosis score (FibroTest), in vivo Tc-99m DTPA measurement of glomerular filtration rate (mGFR), and urine albumin-creatinine ratio (ACR). RESULTS: Mean age and time since Fontan were 19.8 ±â€¯9.3 and 14.1 ±â€¯7.6 years, respectively. Features suggestive of hepatic fibrosis were observed on ultrasound in 87/143 (61%) and no patient was diagnosed with hepatocellular carcinoma. FibroScan median kPa was ≥10 in 117/133 (88%), ≥15 in 75/133 (56%), and ≥20 in 41/133 (31%). Fifty-four patients (54/118, 46%) had a FibroTest score ≥0.49 (equivalent to ≥F2 fibrosis). FibroTest score correlated with FibroScan value (r = 0.24, p = 0.015) and ACR (r = 0.29, p = 0.002), and patients with ultrasound features of hepatic fibrosis had a higher FibroScan median kPa (19.5 vs 15.4, p = 0.002). Renal impairment was mild (mGFR 60-89 ml/min/1.73 m2) in 46/131 (35%) and moderate (mGFR 30-59 ml/min/1.73 m2) in 3/131 (2%). Microalbuminuria was detected in 52/139 participants (37%). By multivariable analysis, time since Fontan was associated with increased FibroScan median kPa (ß = 0.89, 95% CI 0.54-1.25, p = 0.002) and decreased mGFR (ß = -0.77, 95% CI -1.29-0.24, p = 0.005). CONCLUSIONS: In the second decade after Fontan hepatic and renal structure and function are abnormal in a significant number of patients: close to 60% have ultrasonographic evidence of structural hepatic abnormalities, 46% have elevated serum hepatic fibrosis scores, and 57% have either reduced glomerular filtration rate or microalbuminuria. Hepatic and renal function should be monitored for potential impacts on outcomes after Fontan completion.

Risk factors and clinical features of acute pulmonary embolism in children from the community.

BACKGROUND AND AIMS: Current clinical decision rules for pulmonary embolism are based on adult populations and have not been validated in children. The objective was to identify and evaluate clinical features for a first lifetime episode of pulmonary embolism in children presenting to the emergency department. MATERIALS AND METHODS: We present a case-control study of children (≤18years) presenting to the emergency department of the Royal Children's Hospital, Melbourne between November 2007 and February 2015. Children with radiologically proven pulmonary embolism formed the case group, whilst children in whom there was a clinical suspicion of pulmonary embolism but negative diagnostic imaging formed the control group. Charts, electronic medical and imaging records of both cases and controls were reviewed and analysed. RESULTS: There were a total of 50 patients in this study (11 cases and 39 controls). Current or recent (within three months) use of the oral contraceptive pill was the most significant risk factor in our study (odds ratio 14.667, 95% confidence interval 3.001-71.678, P<0.001). Most other features failed to discriminate between cases and controls, although there was a trend towards increased heart rate in cases. CONCLUSIONS: Pulmonary embolism is perhaps the most common presenting spontaneous venous thromboembolism in the community and teenage girls on the oral contraceptive pill are most at-risk amongst children. The clinical signs and symptoms are often non-specific. Additional larger studies are required to determine the significance and magnitude of potential clinical predictors identified in this study. This may lead to derivation of a paediatric-specific pre-test probability tool.

Managing knowledge and technology to foster innovation at the Ohio State University Medical Center.

Biomedical knowledge is expanding at an unprecedented rate-one that is unlikely to slow anytime in the future. While the volume and scope of this new knowledge poses significant organizational challenges, it creates tremendous opportunities to release and direct its power to the service of significant goals. The authors explain how the Center for Knowledge Management at The Ohio State University Medical Center, created during the academic year 2003-04, is doing just that by integrating numerous resource-intensive, technology-based initiatives-including personnel, services and infrastructure, digital repositories, data sets, mobile computing devices, high-tech patient simulators, computerized testing, and interactive multimedia-in a way that enables the center to provide information tailored to the needs of students, faculty and staff on the medical center campus and its surrounding health sciences colleges. The authors discuss how discovering, applying, and sharing new knowledge, information assets, and technologies in this way is a collaborative process. This process creates open-ended opportunities for innovation and a roadmap for working toward seamless integration, synergy, and substantial enhancement of the academic medical center's research, educational, and clinical mission areas.

Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians.

OBJECTIVE: To assess the cancer risk in children and adolescents following exposure to low dose ionising radiation from diagnostic computed tomography (CT) scans. DESIGN: Population based, cohort, data linkage study in Australia. COHORT MEMBERS: 10.9 million people identified from Australian Medicare records, aged 0-19 years on 1 January 1985 or born between 1 January 1985 and 31 December 2005; all exposures to CT scans funded by Medicare during 1985-2005 were identified for this cohort. Cancers diagnosed in cohort members up to 31 December 2007 were obtained through linkage to national cancer records. MAIN OUTCOME: Cancer incidence rates in individuals exposed to a CT scan more than one year before any cancer diagnosis, compared with cancer incidence rates in unexposed individuals. RESULTS: 60,674 cancers were recorded, including 3150 in 680,211 people exposed to a CT scan at least one year before any cancer diagnosis. The mean duration of follow-up after exposure was 9.5 years. Overall cancer incidence was 24% greater for exposed than for unexposed people, after accounting for age, sex, and year of birth (incidence rate ratio (IRR) 1.24 (95% confidence interval 1.20 to 1.29); P<0.001). We saw a dose-response relation, and the IRR increased by 0.16 (0.13 to 0.19) for each additional CT scan. The IRR was greater after exposure at younger ages (P<0.001 for trend). At 1-4, 5-9, 10-14, and 15 or more years since first exposure, IRRs were 1.35 (1.25 to 1.45), 1.25 (1.17 to 1.34), 1.14 (1.06 to 1.22), and 1.24 (1.14 to 1.34), respectively. The IRR increased significantly for many types of solid cancer (digestive organs, melanoma, soft tissue, female genital, urinary tract, brain, and thyroid); leukaemia, myelodysplasia, and some other lymphoid cancers. There was an excess of 608 cancers in people exposed to CT scans (147 brain, 356 other solid, 48 leukaemia or myelodysplasia, and 57 other lymphoid). The absolute excess incidence rate for all cancers combined was 9.38 per 100,000 person years at risk, as of 31 December 2007. The average effective radiation dose per scan was estimated as 4.5 mSv. CONCLUSIONS: The increased incidence of cancer after CT scan exposure in this cohort was mostly due to irradiation. Because the cancer excess was still continuing at the end of follow-up, the eventual lifetime risk from CT scans cannot yet be determined. Radiation doses from contemporary CT scans are likely to be lower than those in 1985-2005, but some increase in cancer risk is still likely from current scans. Future CT scans should be limited to situations where there is a definite clinical indication, with every scan optimised to provide a diagnostic CT image at the lowest possible radiation dose.

How common is colonic elongation in children with slow-transit constipation or anorectal retention?

PURPOSE: Colonic elongation is reported as a possible cause for slow colonic transit, as it is observed in patients with slow-transit constipation (STC). This study aimed to determine the frequency of colonic elongation in children with STC or anorectal retention using radioimaging. We hypothesized that transverse colon elongation may occur in patients with STC, whereas sigmoid colon elongates in patients with anorectal retention. METHODS: Nuclear transit scintigraphy performed for chronic constipation (1999-2011) was analyzed qualitatively for elongated transverse colon or sigmoid colon. Three major colonic transit patterns were identified: slow transit in the proximal colon (STC), normal proximal colonic transit with anorectal retention (NT-AR), and rapid proximal transit ± anorectal retention (RT). χ(2) Test was used for statistical analysis (P < .05 significant). RESULTS: From 1999 to 2011, 626 children had nuclear transit scintigraphy. Transverse colon elongation occurred more frequently in STC (73/322, or 23%) compared with NT-AR (9/127, or 7%) and RT (5/177, or 3%; P < .0001). Sigmoid colon elongation was equally common in NT-AR (8/127, or 6%) compared with RT (10/177, or 6%) and STC (14/322, or 4%; P < .9). CONCLUSION: Transverse colon elongation is more common in STC (23%), whereas sigmoid colon elongation is not more common in anorectal retention. Colonic elongation may be the cause or the result of the underlying slow colonic transit.

Paediatric CT imaging trends in Australia.

INTRODUCTION: The use of CT has rapidly increased since its introduction. Although an important medical tool for diagnosis and treatment, CT is recognised as being among the highest contributors to population radiation exposure. As the risks associated with exposure are higher for children than for adults, this study assessed the impact of paediatric CT in Australia by analysing imaging trends. METHODS: CT imaging trends were derived from Medicare data. Comparable data from a dedicated paediatric hospital (Royal Children's Hospital Melbourne (RCH)) were analysed to determine the validity of utilising Medicare statistics in the younger age groups. The resulting trends reflect the situation for paediatric CT imaging in Australia. RESULTS: In 2009, 2.1 million CT services were billed to Medicare in Australia for children and adults. The average annual growth in the number of CT services provided since 1994 was 8.5%, compared with population growth of 1.4%. Comparison of RCH and Medicare data revealed that only one third of paediatric CT imaging is captured by Medicare. Combining the data sets showed that over the last 20 years, there has been an average annual increase of 5.1% in the CT imaging rate for 0 to 18-year-olds. However, in recent years, growth in the imaging rate for 11 to 18-year-olds has slowed, while for 5 to 10-year-olds the imaging rate has declined. CONCLUSIONS: The significant growth in CT services is attributable to increased demand from the adult demographic. Conversely, increases in the imaging rate for paediatric patients have slowed overall. In fact, for some age groups the rate has fallen.

Nuclear transit studies of patients with intractable chronic constipation reveal a subgroup with rapid proximal colonic transit.

AIMS/BACKGROUND: Nuclear transit studies (NTS) allow us to follow transit through the stomach and the small and large intestines. We identified children with chronic constipation with rapid proximal colonic transit and characterized their clinical features. METHODS: We reviewed NTS from 1998 to 2009 to identify patients with chronic constipation and rapid proximal colonic transit, defined as greater than 25% of tracer beyond hepatic flexure at 6 hour and/or greater than 25% of tracer beyond end of descending colon at 24 hour. This was correlated with clinical symptoms and outcome from patient records. RESULTS: Five hundred twenty children with chronic constipation underwent investigation by NTS, and 64 (12%) were identified with rapid proximal colonic transit. The clinical history, symptoms, and outcome in 55 of 64 available for analysis frequently showed family history of allergy (10.9%) and symptoms associated with food allergy/intolerance: abdominal pain (80%), anal fissure (27.3%), and other allergic symptoms (43.6%). Eighteen children were treated with dietary exclusion, with resolution of symptoms in 9 (50%). CONCLUSIONS: Some children with intractable chronic constipation have rapid proximal colonic transit, have symptoms consistent with possible food allergy/intolerance, and may respond to dietary exclusion. The NTS can identify these patients with rapid proximal transit that may be secondary to food intolerance.

NF-kappaB is a negative regulator of IL-1beta secretion as revealed by genetic and pharmacological inhibition of IKKbeta.

IKKbeta-dependent NF-kappaB activation plays a key role in innate immunity and inflammation, and inhibition of IKKbeta has been considered as a likely anti-inflammatory therapy. Surprisingly, however, mice with a targeted IKKbeta deletion in myeloid cells are more susceptible to endotoxin-induced shock than control mice. Increased endotoxin susceptibility is associated with elevated plasma IL-1beta as a result of increased pro-IL-1beta processing, which was also seen upon bacterial infection. In macrophages enhanced pro-IL-1beta processing depends on caspase-1, whose activation is inhibited by NF-kappaB-dependent gene products. In neutrophils, however, IL-1beta secretion is caspase-1 independent and depends on serine proteases, whose activity is also inhibited by NF-kappaB gene products. Prolonged pharmacologic inhibition of IKKbeta also augments IL-1beta secretion upon endotoxin challenge. These results unravel an unanticipated role for IKKbeta-dependent NF-kappaB signaling in the negative control of IL-1beta production and highlight potential complications of long-term IKKbeta inhibition.