Abstract
Background
Rapid 1-hour infliximab infusions have been safely implemented in adults, but studies of these rapid infusions in pediatric patients are limited. This study's primary objective ...was to determine the safety of 1-hour infliximab infusions compared with standard 2- to 3-hour infusions in children with inflammatory bowel disease and other autoimmune disorders.
Methods
We conducted an institutional review board-approved prospective study using an unmatched historical control group at a freestanding children's hospital comparing rapid vs standard infusion rates of infliximab and the use of premedications and immunomodulatory agents on the frequency of early and delayed infusion reactions.
Results
There were 50 subjects with 540 total standard (2- to 3-hour) infusions in the retrospective group and 66 subjects with 545 total rapid (1-hour) infusions assessed in the prospective group. Although the prospective group received a significantly higher infliximab dose, was significantly less likely to receive premedication, and was significantly more likely to receive another immunomodulatory agent, only 2 instances of potential infusion reactions occurred in the 545 rapid infusions (0.36%; 95% confidence interval CI, 0.22%-11.01%; 3% of patients) administered in the prospective group compared with 1 documented infusion reaction (0.19%; 95% CI, 0.0%-11.47%; 2% of patients) in the retrospective group (odds ratio, 0.65; 95% CI, 0.01-12.93; P = 0.99).
Conclusions
This study suggests that rapid infusion of infliximab over 1 hour is not associated with an increased risk of infusion reactions when compared with standard 2- to 3-hour infusions and can be safely used in children with no previous reaction to standard infusions to treat inflammatory bowel disease and other autoimmune diseases.
The authors investigated the usefulness of an approach combining biliopancreatic diversion (BPD) with duodenal switch (DS) and laparoscopic adjustable gastric banding (LAGB) in morbidly obese ...patients.
258 morbidly obese patients underwent bariatric surgery. 80 underwent gastric bypass (GBP), with an 80-ml pouch, a 120-150-cm common channel and a 350-cm alimentary limb (Group 1). 178 underwent BPD combined with DS-LAGB (Group 2): an 80 cm common channel and a 200-cm alimentary limb were created in 68 patients (Subgroup 2a); a 120-cm common channel and a 300-cm alimentary limb were created in 110 patients (Subgroup 2b). Quality of life was assessed using the Moorehead-Ardelt Quality of Life Questionnaire (MA-QLQ).
At 2 years, mean BMI and %EWL were 27.8 kg/m2 and 77.4 (Group 1), 25.2 kg/m2 and 99.6 (Subgroup 2a), and 27.6 kg/m2 and 79.3 (Subgroup 2b), respectively. 4 GBP patients regained their weight 2 years after surgery. There was 1 death, not related to surgery in Subgroup 2b. Preoperative MA-QLQ scores were similar between groups; at 2 years, MA-QLQ scores were higher in Subgroups 2a and 2b compared to Group 1 (+2.49 and +2.59 vs +0.98, respectively).
Combination bariatric surgery is a safe, effective and durable weight loss option for the treatment of morbid obesity.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
OBJECTIVES:
Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies—lipoproteins play critical roles in clearing pathogens from the bloodstream. We ...investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes.
DESIGN:
Genetic and clinical epidemiology, and experimental models.
SETTING:
Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab ODYSSEY OUTCOMES; NCT01663402), and experimental murine models of sepsis.
PATIENTS OR SUBJECTS:
Nine human cohorts with sepsis (total
n
= 12,514) were assessed for an association between sepsis mortality and
PCSK9
loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in
Pseudomonas aeruginosa
and
Staphylococcus aureus
bacteremia sepsis models, and in lipopolysaccharide-induced animal models.
INTERVENTIONS:
Observational human cohort studies used genetic
PCSK9
LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis.
MEASUREMENTS AND MAIN RESULTS:
Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic
PCSK9
LOF was odds ratio = 0.86 (95% CI, 0.67–1.10;
p
= 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32–1.20;
p
= 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival.
CONCLUSIONS:
PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.
Objective
To identify early factors associated with disease course in patients with juvenile idiopathic inflammatory myopathies (IIMs).
Methods
Univariable and multivariable multinomial logistic ...regression analyses were performed in a large juvenile IIM registry (n = 365) and included demographic characteristics, early clinical features, serum muscle enzyme levels, myositis autoantibodies, environmental exposures, and immunogenetic polymorphisms.
Results
Multivariable associations with chronic or polycyclic courses compared to a monocyclic course included myositis‐specific autoantibodies (multinomial odds ratio OR 4.2 and 2.8, respectively), myositis‐associated autoantibodies (multinomial OR 4.8 and 3.5), and a documented infection within 6 months of illness onset (multinomial OR 2.5 and 4.7). A higher overall clinical symptom score at diagnosis was associated with chronic or monocyclic courses compared to a polycyclic course. Furthermore, severe illness onset was associated with a chronic course compared to monocyclic or polycyclic courses (multinomial OR 2.1 and 2.6, respectively), while anti‐p155/140 autoantibodies were associated with chronic or polycyclic courses compared to a monocyclic course (multinomial OR 3.9 and 2.3, respectively). Additional univariable associations of a chronic course compared to a monocyclic course included photosensitivity, V‐sign or shawl sign rashes, and cuticular overgrowth (OR 2.2–3.2). The mean ultraviolet index and highest ultraviolet index in the month before diagnosis were associated with a chronic course compared to a polycyclic course in boys (OR 1.5 and 1.3), while residing in the Northwest was less frequently associated with a chronic course (OR 0.2).
Conclusion
Our findings indicate that myositis autoantibodies, in particular anti‐p155/140, and a number of early clinical features and environmental exposures are associated with a chronic course in patients with juvenile IIM. These findings suggest that early factors, which are associated with poorer outcomes in juvenile IIM, can be identified.
Full text
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We have previously described an allelic polymorphism in the Vβ6.1 T-cell receptor gene. The Vβ6.1B allele is associated with disease in a subgroup of patients with juvenile rheumatoid arthritis. ...Limited sequence data demonstrated nucleotide differences that resulted in two amino acid changes between the two alleles in positions predicted to be important in major histocompatibility complex/antigen recognition. The present study demonstrates substantially reduced expression of mRNA from the disease-associated allele (Vβ6.1B) in peripheral blood and thymic tissue. The complete genomic sequence of both alleles revealed two additional amino acid changes in the Vβ6.1B gene as well as nucleotide differences in the promoter and intron. A cysteine-to-arginine substitution at position 92 in the disease-associated allele makes this a non-functional β chain, since this conserved cysteine is involved with disulfide bonding to cysteine-23 to form an immunoglobulin-like domain structure, thus resulting in a potential hole in the T-cell receptor repertoire.
Full text
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
A case study of a patient with juvenile rheumatoid arthritis who developed acquired circulating inhibitor to factor VIII is presented. An overview of research on the condition is presented.
Children with juvenile rheumatoid arthritis (JRA) may develop an acquired circulating inhibitor to blood clotting factor VIII (FVIII), which has also been found in hemophiliacs. JRA is a chronic ...disease of children involving inflammation of the joints. A 19-year-old man with JRA whose FVIII activity was found to be very low was then found to have the acquired FVIII inhibitor. Patients with acquired FVIII inhibitor usually have bleeding complications similar to those seen in hemophiliacs. Eighteen pediatric cases of acquired FVIII inhibitor were found in the literature, but only this case described JRA as well. Aggressive early treatment with corticosteroids and, later on, cyclophosphamide, was given to this patient. Although rare, it is suggested that acquired FVIII inhibitor be considered as a cause of bleeding disorder in children with JRA.
This report demonstrates a T-cell receptor (Tcr) restriction fragment length polymorphism, defined by a Tcrb-V6.1 gene probe and Bgl II restriction enzyme, to be absolutely correlated with allelic ...variation in the coding sequence of a Tcrb-V6.1 gene. A pair of non-conservative amino acid substitutions distinguish the Tcrb-V6.1 allelic variants. An association of this Tcrb-V6.1 gene allelic variant with one form of juvenile rheumatoid arthritis (JRA) was established in a cohort of 126 patients. The association was observed in patients possessing the HLA-DQA1*0101 gene. Among HLA-DQA*0101 individuals, 19 of 26 patients (73.1%) carried one particular Tcrb-V6.1 gene allele as opposed to 11 of 33 controls (33%; p less than 0.005). Haplotypes carrying this HLA gene have previously been shown to confer increased risk for progression of arthritis in JRA. This demonstration of a disease-associated Tcrb-V gene allelic variant has not, to our knowledge, been previously reported and supports the contribution of polymorphism in the Tcr variable region genomic repertoire to human autoimmune disease.
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