Preliminary Evidence for the Role of Fungi, Specifically Chaetomium, in Gulf War Illness.

INTRODUCTION: For veterans of the Persian Gulf War (1990-1991), dozens of possible causes for their illness have been proposed. We hypothesize that all may be correct. These may have weakened the immunity of the military personnel to fungal pathogens in the soil. These microbes, in turn, may have afflicted the veterans either directly by infection or indirectly by toxins. MATERIALS AND METHODS: In 1990, the military (source confidential) provided the first author with soil samples from the Persian Gulf to determine if there were biothreats present. His team found that per gram of soil, there had few bacteria but many fungi. The National Centre for Human Mycotic Diseases (Edmonton) identified some of these fungi. They sent to the first author reference cultures of 12 pathogenic fungal species isolated from Canadian patients. Supernatant antigens of these fungi were used to assess if control and Gulf War Illness (GWI) patient sera had IgG antibodies against them. RESULTS: Human sera were tested on pathogenic fungal supernatant antigens. Controls had low IgG titers against all 12 fungal sources. Gulf War Illness (GWI) patient sera had low IgG titers against 11 of the 12 fungal antigens. However, 12 of 28 GWI patient sera (43%, P ≤ .0002 compared to controls) had high IgG titers against one fungus, Chaetomium, supernatant antigen. CONCLUSIONS: We suggest that the military personnel in the Persian Gulf War (1990-1991) may have had their immunity weakened from a variety of causes. The role of pathogenic fungi and/or their supernatant antigens or toxins as a contributing factor to GWI should be further investigated.

Realizing the Potential of the Patient Perspective.

Assessing a patient's perspective on their treatment is part of an increasingly integrated approach to pharmacovigilance and treatment optimization. New tools and methods developed in partnership with patients can capture and quantify cognitive and behavioral aspects of the treatment experience. These treatment insights have the potential to shape the drug development process, as well as supplement patient-reported outcome data in a way that is meaningful to the patient. We highlight examples of tools developed to assess the impact of treatment on the aspects of disease that are of utmost concern to the patient in their daily life.

Abatacept: A Review of the Treatment of Polyarticular-Course Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) encompasses several forms of chronic inflammatory arthritis of unknown etiology presenting in children < 16 years of age, with a minimum symptom duration of 6 weeks. Approximately half of affected children have polyarticular-course JIA (pJIA), a functional concept related to several clinically and genetically heterogeneous JIA categories (systemic, extended oligoarthritis, polyarticular rheumatoid factor-positive or rheumatoid factor-negative, enthesitis-related arthritis, and psoriatic arthritis), which has as its defining feature the involvement of five or more joints during the disease course. Chronic inflammation and joint damage lead to the manifestations of JIA such as pain, limitation of motion, and loss of physical function, all of which negatively impact patients' quality of life. The American College of Rheumatology recommends initial treatment with a conventional synthetic disease-modifying antirheumatic drug (csDMARD), such as methotrexate (MTX) and, in patients with pJIA who have an inadequate response or intolerance to MTX, the use of a biologic DMARD (bDMARD) such as a tumor necrosis factor inhibitor, abatacept, or tocilizumab. Abatacept selectively modulates the CD80/CD86:CD28 co-stimulatory signal required for full T cell activation, and thus has a distinct mechanism of action upstream of that of other currently available bDMARD treatments for rheumatic diseases. To enable physicians to make informed treatment decisions, it is important to review available data for the existing therapeutic agents. Here, we summarize the current evidence from phase III pivotal trials of intravenous (IV) and subcutaneous (SC) abatacept and from an ongoing registry of patients with JIA treated with abatacept. In the pivotal trials for IV and SC abatacept, either with or without MTX, both formulations demonstrated clinical efficacy, with a high proportion of patients achieving stringent clinical responses, as well as improvements in patient-reported outcomes and a favorable safety profile, particularly with regard to infections.

Comparing record linkage software programs and algorithms using real-world data.

Linkage of medical databases, including insurer claims and electronic health records (EHRs), is increasingly common. However, few studies have investigated the behavior and output of linkage software. To determine how linkage quality is affected by different algorithms, blocking variables, methods for string matching and weight determination, and decision rules, we compared the performance of 4 nonproprietary linkage software packages linking patient identifiers from noninteroperable inpatient and outpatient EHRs. We linked datasets using first and last name, gender, and date of birth (DOB). We evaluated DOB and year of birth (YOB) as blocking variables and used exact and inexact matching methods. We compared the weights assigned to record pairs and evaluated how matching weights corresponded to a gold standard, medical record number. Deduplicated datasets contained 69,523 inpatient and 176,154 outpatient records, respectively. Linkage runs blocking on DOB produced weights ranging in number from 8 for exact matching to 64,273 for inexact matching. Linkage runs blocking on YOB produced 8 to 916,806 weights. Exact matching matched record pairs with identical test characteristics (sensitivity 90.48%, specificity 99.78%) for the highest ranked group, but algorithms differentially prioritized certain variables. Inexact matching behaved more variably, leading to dramatic differences in sensitivity (range 0.04-93.36%) and positive predictive value (PPV) (range 86.67-97.35%), even for the most highly ranked record pairs. Blocking on DOB led to higher PPV of highly ranked record pairs. An ensemble approach based on averaging scaled matching weights led to modestly improved accuracy. In summary, we found few differences in the rankings of record pairs with the highest matching weights across 4 linkage packages. Performance was more consistent for exact string matching than for inexact string matching. Most methods and software packages performed similarly when comparing matching accuracy with the gold standard. In some settings, an ensemble matching approach may outperform individual linkage algorithms.

Changes in Receipt of Cancer Screening in Medicare Beneficiaries Following the Affordable Care Act.

BACKGROUND: The Affordable Care Act (ACA) removed copayments for screening mammography and colonoscopy in Medicare beneficiaries, but its clinical impact is unknown. METHODS: Using a 5% random sample of Medicare claims from 2009 through 2012 in individuals age 70 years or older who were due for screening, we examined claims for screening mammography and screening or surveillance colonoscopy for two years prior to ACA (2009-2010) and two years post-ACA (2011-2012). Receipt of the procedures at the patient level was compared across years using generalized estimating equations. Statistical tests were two-sided. RESULTS: Compared with 2009, we found an increase in mammography uptake during the ACA coverage period, with multivariable odds ratios (MOR) of 1.22 (95% confidence interval [CI] = 1.20 to 1.25, P < .001) for 2011 and 1.17 (95% CI = 1.15 to 1.20, P < .001) for 2012 and less change in 2010 (OR = 1.03, 95% CI = 1.01 to 1.05, P = .01). In contrast to mammography, uptake of screening or surveillance colonoscopy decreased in 2012 (MOR = 0.95, 95% CI = 0.92 to 0.98, P = .002) compared with 2009, with no change in 2010 (MOR = 1.01, 95% CI = 0.99 to 1.04, P = .47) or 2011 (MOR = 1.01, 95% CI = 0.99 to 1.04, P = .34). Other factors associated with procedure receipt included younger age and prior preventive health visits. In an analysis restricted to patients age 70 to 74 years, colonoscopy use increased slightly in 2011 but was unchanged in 2012, and the findings by year for mammography were consistent with the main analysis. CONCLUSIONS: Following ACA implementation with concomitant reduction in out-of-pocket expenditures, there was a statistically significant increment in mammography uptake but not colonoscopy. This suggests that affordability is a necessary but not sufficient facilitator of preventive services.

Complications following colonoscopy with anesthesia assistance: a population-based analysis.

IMPORTANCE: Deep sedation for endoscopic procedures has become an increasingly used option but, because of impairment in patient response, this technique also has the potential for a greater likelihood of adverse events. The incidence of these complications has not been well studied at a population level. DESIGN: Population-based study. SETTING AND PARTICIPANTS: Using a 5% random sample of cancer-free Medicare beneficiaries who resided in one of the regions served by a SEER (Surveillance, Epidemiology, and End Results) registry, we identified all procedural claims for outpatient colonoscopy without polypectomy from January 1, 2000, through November 30, 2009. INTERVENTION: Colonoscopy without polypectomy, with or without the use of deep sedation (identified by a concurrent claim for anesthesia services). MAIN OUTCOME MEASURES: The occurrence of hospitalizations for splenic rupture or trauma, colonic perforation, and aspiration pneumonia within 30 days of the colonoscopy. RESULTS: We identified a total of 165 527 procedures in 100 359 patients, including 35 128 procedures with anesthesia services (21.2%). Selected postprocedure complications were documented after 284 procedures (0.17%) and included aspiration (n = 173), perforation (n = 101), and splenic injury (n = 12). (Some patients had >1 complication.) Overall complications were more common in cases with anesthesia assistance (0.22% [95% CI, 0.18%-0.27%]) than in others (0.16% [0.14%-0.18%]) (P < .001), as was aspiration (0.14% [0.11%-0.18%] vs 0.10% [0.08%-0.12%], respectively; P = .02). Frequencies of perforation and splenic injury were statistically similar. Other predictors of complications included age greater than 70 years, increasing comorbidity, and performance of the procedure in a hospital setting. In multivariate analysis, use of anesthesia services was associated with an increased complication risk (odds ratio, 1.46 [95% CI, 1.09-1.94]). CONCLUSIONS AND RELEVANCE: Although the absolute risk of complications is low, the use of anesthesia services for colonoscopy is associated with a somewhat higher frequency of complications, specifically, aspiration pneumonia. The differences may result in part from uncontrolled confounding, but they may also reflect the impairment of normal patient responses with the use of deep sedation.

Use of colonoscopy for polyp surveillance in Medicare beneficiaries.

BACKGROUND: Professional society guidelines recommend follow-up colonoscopy for patients with resected colonic adenomas. However, adherence to guideline recommendations in routine clinical practice has not been well characterized. METHODS: The authors used a population-based sample of Medicare beneficiaries to identify all patients aged ≥70 years who had a claim for colonoscopy with polypectomy or hot biopsy during the period from 2001 to 2004. Medicare claims through 2009 identified colonoscopy within the following 5 years as well as fecal occult blood testing, sigmoidoscopy, and barium enema. RESULTS: In total, 12,771 patients were included. At 5 years, 45.7% of patients underwent another colonoscopy, and 32.3% of procedures included a polypectomy. The rates of fecal occult blood testing, flexible sigmoidoscopy, and barium enema at 5 years were 54%, 3.8%, and 2.9%, respectively. There was a marked decrease in repeat colonoscopy at 1 year, 3 years, and 5 years with more recent years of index procedures. Other predictors of undergoing repeat colonoscopy were younger age, African American race, and a colonoscopy before the index examination. There was no association with physician specialty. The decreasing use of colonoscopy with time was maintained in a multivariable analysis. CONCLUSIONS: In a sample of elderly Medicare beneficiaries, there was under use of follow-up colonoscopy at 5 years after polypectomy, and <50% of patients received a repeat examination. In particular, the use of this procedure decreased over the 4-year study period. Coupled with other data indicating the overuse of follow-up colonoscopy in patients without polyps, there appeared to be significant discordance between guidelines and actual practice.

Risk of upper gastrointestinal tract events in risedronate users switched to alendronate.

Upper gastrointestinal (GI) side effects are a known complication of therapy with oral aminobisphosphonates, but it is currently unclear if bisphosphonate type or formulation influences the risk of developing side effects. Here, we performed a retrospective cohort study to determine if patients who switched from weekly risedronate to weekly alendronate had an increased risk of upper GI side events. The study utilized The Health Improvement Network (THIN) database, which contained anonymous medical records from 390 general practices in the United Kingdom. The study was performed following the introduction of generic alendronate preparations, by which point 94% of alendronate prescriptions were for the generic formulation. We identified 3,446 patients who had been stabilized on risedronate 35 mg/week, of whom 530 were switched to alendronate 70 mg/week. The risk of developing a GI adverse event was higher in patients who switched to alendronate compared with those who remained on risedronate (hazard ratio [HR] = 1.85, 95% confidence interval [CI] 1.26-2.72). The risk was even greater in the subgroup of patients with a history of upper GI events (HR = 3.18, 95% CI 2.79-3.63) but was also observed in patients with no history of GI events (HR = 1.76, 95% CI 1.15-2.69). We conclude that switching patients who are stabilized on risedronate to alendronate is associated with an increased risk of GI adverse effects. This could lead to reduced compliance and reduced therapeutic effectiveness, which might offset the cost savings of using the generic formulation.

Ischemia/reperfusion: a clinically relevant model of intestinal injury yielding systemic inflammation.

BACKGROUND/PURPOSE: Multisystem organ failure (MSOF) is a major cause of morbidity and mortality in the critically ill patient. Animal models of endotoxin-induced sepsis were used to develop therapeutic regimens, which thus far have failed in clinical trials. Because multiple etiologies of MSOF affect the intestine, the authors hypothesized that during sepsis the gut may act as a possible trigger of the inflammatory cascade. As ischemia and reperfusion of the small intestine disrupts gut barrier function, thereby activating systemic inflammatory responses, the authors evaluated a murine model of ischemia/reperfusion to investigate these systemic responses to local mucosal and epithelial injury. METHODS: C57BL/10 and Balb/c mice underwent variable amounts of gut ischemia by superior mesenteric artery occlusion. Animals were evaluated for survival as well as gross and microscopic intestinal damage. RESULTS: Maximal ischemic damage occurred in the distal jejunum and proximal ileum. More severe epithelial damage and transmural inflammation were observed in C57BL/10 mice, which correlated with a higher mortality. CONCLUSIONS: This model mimics what is observed clinically with intestinal injury resulting from a progressive ischemic insult with eventual systemic manifestations. This reproducible model of systemic inflammation elicits variable responses from genetically different animals, the results of which may lead to a better understanding of MSOF.

IL-10 is not protective in intestinal ischemia reperfusion injury.

BACKGROUND: Ischemia/reperfusion of the small intestine disrupts gut barrier function, increases bacterial translocation, and activates systemic pro-inflammatory responses. Pharmacological treatment with the anti-inflammatory cytokine interleukin-10 (IL-10) following ischemia to muscle reduces the severity of local and systemic inflammation. While endogenous IL-10 is protective in murine models of acute endotoxemia, its physiological role during direct gut injury is unknown. PATIENTS AND MATERIALS: Mice genetically deficient in IL-10 (IL-10(-/-)) and their normal littermates (IL-10(+/+)) underwent 20 to 50 min of gut ischemia by occlusion of the superior mesenteric artery. RESULTS: Both short- and long-term (>16 h) survival after reperfusion of IL-10(-/-) mice was identical to that of the wild-type littermates, with 50% mortality observed at 35 min of occlusion. The small bowel demonstrated discrete gross areas of hemorrhage and ischemia localized to the jejunum. No significant difference in the extent or time for occurrence of macroscopic or microscopic intestinal damage to the small bowel was observed in IL-10(-/-) or IL-10(+/+) mice, despite the marked elevation in serum IL-6. CONCLUSIONS: The absolute serum concentration of IL-6 in the presence or the absence of IL-10 does not affect local or systemic response to ischemic intestinal injury. These results also demonstrate that the anti-inflammatory cytokine IL-10 does not play a significant local or systemic protective role in this model of ischemia/reperfusion.