Background The B-cell receptor transmembrane activator and calcium modulator ligand interactor (TACI) is important for T-independent antibody responses. One in 200 blood donors are heterozygous for ...the TACI A181E mutation. Objective We sought to investigate the effect on B-cell function of TACI A181E heterozygosity in reportedly healthy subjects and of the corresponding TACI A144E mutation in mice. Methods Nuclear factor κB (NF-κB) activation was measured by using the luciferase assay in 293T cells cotransfected with wild-type and mutant TACI. TACI-driven proliferation, isotype switching, and antibody responses were measured in B cells from heterozygous TACI A144E knock-in mice. Mouse mortality was monitored after intranasal pneumococcal challenge. Results Levels of natural antibodies to the pneumococcal polysaccharide component phosphocholine were significantly lower in A181E-heterozygous than TACI-sufficient Swedish blood donors never immunized with pneumococcal antigens. Although overexpressed hTACI A181E and mTACI A144E acted as dominant-negative mutations in transfectants, homozygosity for A144E in mice resulted in absent TACI expression in B cells, indicating that the mutant protein is unstable when naturally expressed. A144E heterozygous mice, such as TACI+/− mice, expressed half the normal level of TACI on their B cells and exhibited similar defects in a proliferation-inducing ligand–driven B-cell activation, antibody responses to TNP-Ficoll, production of natural antibodies to phosphocholine, and survival after intranasal pneumococcal challenge. Conclusion These results suggest that TACI A181E heterozygosity results in TACI haploinsufficiency with increased susceptibility to pneumococcal infection. This has important implications for asymptomatic TACI A181E carriers.
Objective To evaluate the health benefits of an exclusively human milk–based diet compared with a diet of both human milk and bovine milk–based products in extremely premature infants. Study design ...Infants fed their own mothers' milk were randomized to 1 of 3 study groups. Groups HM100 and HM40 received pasteurized donor human milk–based human milk fortifier when the enteral intake was 100 and 40 mL/kg/d, respectively, and both groups received pasteurized donor human milk if no mother's milk was available. Group BOV received bovine milk–based human milk fortifier when the enteral intake was 100 mL/kg/d and preterm formula if no mother's milk was available. Outcomes included duration of parenteral nutrition, morbidity, and growth. Results The 3 groups (total n = 207 infants) had similar baseline demographic variables, duration of parenteral nutrition, rates of late-onset sepsis, and growth. The groups receiving an exclusively human milk diet had significantly lower rates of necrotizing enterocolitis (NEC; P = .02) and NEC requiring surgical intervention ( P = .007). Conclusions For extremely premature infants, an exclusively human milk–based diet is associated with significantly lower rates of NEC and surgical NEC when compared with a mother's milk–based diet that also includes bovine milk–based products.
Purpose We examined symptom variability in men and women with urological chronic pelvic pain syndrome. We describe symptom fluctuations as related to early symptom regression and its effect on ...estimated 1-year symptom change. We also describe a method to quantify patient specific symptom variability. Materials and Methods Symptoms were assessed biweekly in 424 subjects with urological chronic pelvic pain syndrome during 1 year. To evaluate the impact of early symptom regression subjects were classified as improved, no change or worse according to the rate of change using 1) all data, 2) excluding week 0 and 3) excluding weeks 0 and 2. Patient specific, time varying variability was calculated at each interval using a sliding window approach. Patients were classified as high, medium or low variability at each time and ultimately as high or low variability overall based on the variability for the majority of contacts. Results Prior to excluding early weeks to adjust for early symptom regression 25% to 38% and 5% to 6% of patients were classified as improved and worse, respectively. After adjustment the percent of patients who were improved or worse ranged from 15% to 25% and 6% to 9%, respectively. High and low variability phenotypes were each identified in 25% to 30% of participants. Conclusions Patients with urological chronic pelvic pain syndrome show symptom variability. At study enrollment patients had worse symptoms on average, resulting in a regression effect that influenced the estimated proportion of those who were improved or worse. Prospective studies should include a run-in period to account for regression to the mean and other causes of early symptom regression. Further, symptom variability may be quantified and used to characterize longitudinal symptom profiles of urological chronic pelvic pain syndrome.
Summary Background Stricturing and penetrating complications account for substantial morbidity and health-care costs in paediatric and adult onset Crohn's disease. Validated models to predict risk ...for complications are not available, and the effect of treatment on risk is unknown. Methods We did a prospective inception cohort study of paediatric patients with newly diagnosed Crohn's disease at 28 sites in the USA and Canada. Genotypes, antimicrobial serologies, ileal gene expression, and ileal, rectal, and faecal microbiota were assessed. A competing-risk model for disease complications was derived and validated in independent groups. Propensity-score matching tested the effect of anti-tumour necrosis factor α (TNFα) therapy exposure within 90 days of diagnosis on complication risk. Findings Between Nov 1, 2008, and June 30, 2012, we enrolled 913 patients, 78 (9%) of whom experienced Crohn's disease complications. The validated competing-risk model included age, race, disease location, and antimicrobial serologies and provided a sensitivity of 66% (95% CI 51–82) and specificity of 63% (55–71), with a negative predictive value of 95% (94–97). Patients who received early anti-TNFα therapy were less likely to have penetrating complications (hazard ratio HR 0·30, 95% CI 0·10–0·89; p=0·0296) but not stricturing complication (1·13, 0·51–2·51; 0·76) than were those who did not receive early anti-TNFα therapy. Ruminococcus was implicated in stricturing complications and Veillonella in penetrating complications. Ileal genes controlling extracellular matrix production were upregulated at diagnosis, and this gene signature was associated with stricturing in the risk model (HR 1·70, 95% CI 1·12–2·57; p=0·0120). When this gene signature was included, the model's specificity improved to 71%. Interpretation Our findings support the usefulness of risk stratification of paediatric patients with Crohn's disease at diagnosis, and selection of anti-TNFα therapy. Funding Crohn's and Colitis Foundation of America, Cincinnati Children's Hospital Research Foundation Digestive Health Center.
Study objective Molecular definition of disease has been changing all aspects of medical practice, from diagnosis and screening to understanding and treatment. Acute appendicitis is among many human ...conditions that are complicated by the heterogeneity of clinical presentation and shortage of diagnostic markers. Here, we sought to profile the urine of patients with appendicitis, with the goal of identifying new diagnostic markers. Methods Candidate markers were identified from the urine of children with histologically proven appendicitis by using high-accuracy mass spectrometry proteome profiling. These systemic and local markers were used to assess the probability of appendicitis in a blinded, prospective study of children being evaluated for acute abdominal pain in our emergency department. Tests of performance of the markers were evaluated against the pathologic diagnosis and histologic grade of appendicitis. Results Test performance of 57 identified candidate markers was studied in 67 patients, with median age of 11 years, 37% of whom had appendicitis. Several exhibited favorable diagnostic performance, including calgranulin A (S100-A8), α-1-acid glycoprotein 1 (orosomucoid), and leucine-rich α-2-glycoprotein (LRG), with the receiver operating characteristic area under the curve and values of 0.84 (95% confidence interval CI 0.72 to 0.95), 0.84 (95% CI 0.72 to 0.95), and 0.97 (95% CI 0.93 to 1.0), respectively. LRG was enriched in diseased appendices, and its abundance correlated with severity of appendicitis. Conclusion High-accuracy mass spectrometry urine proteome profiling allowed identification of diagnostic markers of acute appendicitis. Usage of LRG and other identified biomarkers may improve the diagnostic accuracy of clinical evaluations of appendicitis.
Background The Florida Initiative for Quality Cancer Care (FIQCC), composed of 11 practice sites across Florida, conducted its initial evaluation of adherence to breast cancer quality of care ...indicators (QCI) in 2006, with feedback provided to encourage quality improvement efforts at participating sites. In this study, our objective was to reassess changes over time resulting from these efforts. Study Design Quality care indicators were derived from the Quality Oncology Practice Initiative, the National Comprehensive Cancer Network, the American College of Surgeons, and expert panel consensus. Medical records were reviewed for breast cancer patients first seen by medical oncologists in 2009 at the FIQCC sites, using the same performance indicators as in 2006. Statistical comparisons of 2006 vs 2009 data across sites were made by Pearson chi-square exact test using Monte Carlo estimation. Results Charts of 602 patients in 2006 and 636 patients in 2009 were compared. Performance on medical oncology QCI improved over time for documentation of clinical trial participation discussion (p = 0.001), documentation of consent for chemotherapy (p = 0.047), definitive surgery done after neoadjuvant chemotherapy (p = 0.017), and planned dose of chemotherapy consistent with published regimens (p = 0.02). Improvements in surgical QCI were seen for documentation of specimen orientation (p < 0.001), inking of margins (p < 0.0001), and performance of sentinel lymph node biopsy (p = 0.035). Conclusions The 2006 FIQCC study identified several medical and surgical oncology QCI improvement needs. Quality improvement efforts resulted in better performance for numerous metrics, therefore speaking to the benefits of reassessment of adherence to performance indicators to guide QCI efforts.
Background We reviewed reoperations for persistent or recurrent sporadic parathyroid adenoma to evaluate and compare our current results and outcomes to our previous experience. Methods From 1996 to ...2008, 237 patients with persistent or recurrent hyperparathyroidism after failed operation underwent reoperation. Patients were re-explored with the assistance of non-invasive and sometimes invasive imaging. Results A missed adenoma was suspected pre-operatively in 163 patients. Reoperation resulted in long-term resolution of hypercalcemia in 92%. Adenomas were in entopic locations in 32%; the most frequent ectopic location was the thymus (20%). Sestamibi scanning and ultrasonography were the most successful non-invasive imaging studies (96% positive predictive value (PPV) and 84% PPV respectively). Forty-four percent of patients had a reoperation based solely on non-invasive imaging. Of the invasive procedures performed, arteriography resulted in the best localization (92% PPV). Permanent recurrent laryngeal nerve injury occurred in 1.8%. Conclusion Compared to our prior experience (1982–1995), outcomes remained similar (92% resolution of hypercalcemia and 1.8% recurrent nerve injury currently versus 96% and 1.3% previously). Fewer patients received invasive studies for pre-operative localization (56% vs 73%, respectively). The decreased use of invasive imaging is due to technical improvements and greater confidence in the combination of ultrasonography and sestamibi scanning.
Background The classic cut and sew maze is thought to reduce stroke, in part because of left atrial appendage (LAA) elimination. Multiple LAA elimination techniques have evolved with the introduction ...of new surgical treatment options for atrial fibrillation (AF), but the impact on stroke remains unknown. We studied the rate of late neurologic event (LNE) in the era of contemporary AF surgery. Methods From April 21, 2004, to June 30, 2011, 773 patients underwent surgery for AF. In 131 patients, the LAA was excised. In 579, alternative elimination techniques were used (97 external ligation, 313 internal ligation, 126 stapled excision, 23 stapled excision plus internal ligation, 5 internal plus external ligations, and 15 that did not fit into any category); 63 LAAs were left intact and excluded from analyses. Complete follow-up was obtained by medical record review and phone call. Median survival follow-up was 3.3 years (first and third quartiles, 1.6 and 5.0). An LNE was defined as either a documented stroke or transient ischemic attack 30 or more days after surgery. Baseline characteristics and outcomes between LAA techniques were compared using χ2 , Fisher's exact tests, and Student's t tests. Results There were 25 LNEs (3.5%) overall; the median occurrence time was 3.6 years (first and third quartiles, 1.9 and 5.4) after surgery. There were 17 strokes and 8 transient ischemic attacks. Of 45 demographic and surgical variables, only age, aortic valve surgery, and perioperative neurologic event (<30 days after cardiac surgery) independently predicted LNE ( p = 0.003, 0.021, and 0.010, respectively). Late neurologic events occurred with an annual rate of 1.13% in patients with alternative elimination techniques, and 0.20% in patients with excised LAA ( p = 0.001). Patients in AF at any time were more likely to have LNE, but this was not an independent predictor. Conclusions After surgery for AF ablation, there is ongoing low risk of LNE even when the LAA is surgically excised. Further investigation should be pursued to clarify whether a difference exists with alternative elimination techniques and in patients in whom AF is successfully eliminated.
Background The quality of cancer care has become a national priority; however, there are few ongoing efforts to assist medical oncology practices in identifying areas for improvement. The Florida ...Initiative for Quality Cancer Care is a consortium of 11 medical oncology practices that evaluates the quality of cancer care across Florida. Within this practice-based system of self-assessment, we determined adherence to colorectal cancer quality of care indicators (QCIs) in 2006, disseminated results to each practice and reassessed adherence in 2009. The current report focuses on evaluating the direction and magnitude of change in adherence to QCIs for colorectal cancer patients between the 2 assessments. Study Design Medical records were reviewed for all colorectal cancer patients seen by a medical oncologist in 2006 (n = 489) and 2009 (n = 511) at 10 participating practices. Thirty-five indicators were evaluated individually and changes in QCI adherence over time and by site were examined. Results Significant improvements were noted from 2006 to 2009, with large gains in surgical/pathological QCIs (eg, documenting rectal radial margin status, lymphovascular invasion, and the review of ≥12 lymph nodes) and medical oncology QCIs (documenting planned treatment regimen and providing recommended neoadjuvant regimens). Documentation of perineural invasion and radial margins significantly improved; however, adherence remained low (47% and 71%, respectively). There was significant variability in adherence for some QCIs across institutions at follow-up. Conclusions The Florida Initiative for Quality Cancer Care practices conducted self-directed quality-improvement efforts during a 3-year interval and overall adherence to QCIs improved. However, adherence remained low for several indicators, suggesting that organized improvement efforts might be needed for QCIs that remained consistently low over time. Findings demonstrate how efforts such as the Florida Initiative for Quality Cancer Care are useful for evaluating and improving the quality of cancer care at a regional level.
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