The enteroendocrine axis and its effect on gastrointestinal function, nutrition, and inflammation.

PURPOSE OF REVIEW: Gastrointestinal (GI) dysfunction limits enteral nutrition (EN) delivery in critical illness and contributes to systemic inflammation. The enteroendocrine (EE) axis plays an integral role in this interface between nutrition, inflammation, and GI function in critical illness. In this review, we present an overview of the EE system with a focus on its role in GI inflammation and function. RECENT FINDINGS: Enteroendocrine cells have been primarily described in their role in macronutrient digestion and absorption. Recent research has expanded on the diverse functions of EE cells including their ability to sense microbial peptides and metabolites and regulate immune function and inflammation. Therefore, EE cells may be both affected by and contribute to many pathophysiologic states and interventions of critical illness such as dysbiosis , inflammation, and alternative EN strategies. In this review, we present an overview of EE cells including their growing role in nonnutrient functions and integrate this understanding into relevant aspects of critical illness with a focus on EN. SUMMARY: The EE system is key in maintaining GI homeostasis in critical illness, and how it is impacted and contributes to outcomes in the setting of dysbiosis , inflammation and different feeding strategies in critical illness should be considered.

Immune tolerance via FCR001 cell therapy compared with maintenance immunosuppression for kidney transplantation: Real-world evidence analysis of safety and efficacy.

While kidney transplantation (KTx) has traditionally required lifelong immunosuppression, an investigational stem cell therapy, FCR001, has been demonstrated to induce tolerance and eliminate the need for immunosuppression through the establishment of persistent mixed chimerism in a phase 2 clinical study. Real-world evidence (RWE) methods were employed to compare the safety and efficacy of non-myeloablative conditioning with FCR001 with standard of care [SOC] immunosuppression in a retrospective single-center analysis of outcomes among propensity score matched living-donor KTx receiving SOC (n = 144) or FCR001 (n = 36). Among the FCR001 recipients, 26 (72%) developed persistent chimerism allowing durable elimination of all immunosuppression. There was no significant difference in the composite primary endpoint (biopsy-proven acute rejection [BPAR], graft loss, or death) at 60 months (FCR001 27.8%, n = 10 and SOC 28.5%, n = 41; p = .9). FCR001 recipients demonstrated superior kidney function at 5 years (estimated glomerular filtration rate [eGFR] [mean ± standard deviation]: 64.1 ± 15.3) compared to SOC (51.7 ± 18.8; p = .02). At 5 years, FCR001 recipients experienced fewer complications including new-onset diabetes post-transplant, although two patients developed graft versus host disease. In conclusion, RWE demonstrated that KTx combined with non-myeloablative conditioning and FCR001 resulting in superior kidney function without increasing the risk of rejection, graft loss, or death among patients off immunosuppression.

Gut adaptation after gastric bypass in humans reveals metabolically significant shift in fuel metabolism.

OBJECTIVE: Roux-en-Y gastric bypass surgery (RYGB) is among the most effective therapies for obesity and type 2 diabetes, and intestinal adaptation is a proposed mechanism for these effects. It was hypothesized that intestinal adaptation precedes and relates to metabolic improvement in humans after RYGB. METHODS: This was a prospective, longitudinal, first-in-human study of gene expression (GE) in the "Roux limb" (RL) collected surgically/endoscopically from 19 patients with and without diabetes. GE was determined by microarray across six postoperative months, including at an early postoperative (1 month ± 15 days) time point. RESULTS: RL GE demonstrated tissue remodeling and metabolic reprogramming, including increased glucose and amino acid use. RL GE signatures were established early, before maximal clinical response, and persisted. Distinct GE fingerprints predicted concurrent and future improvements in HbA1c and in weight. Human RL exhibited GE changes characterized by anabolic growth and shift in metabolic substrate use. Paradoxically, anabolic growth in RL appeared to contribute to the catabolic state elicited by RYGB. CONCLUSIONS: These data support a role for a direct effect of intestinal energy metabolism to contribute to the beneficial clinical effects of RYGB, suggesting that related pathways might be potential targets of therapeutic interest for patients with obesity with or without type 2 diabetes.

Cognitive behavioral therapy for the treatment of juvenile fibromyalgia: a multisite, single-blind, randomized, controlled clinical trial.

OBJECTIVE: Juvenile fibromyalgia syndrome (FMS) is a chronic musculoskeletal pain disorder in children and adolescents for which there are no evidence-based treatments. The objective of this multisite, single-blind, randomized clinical trial was to test whether cognitive-behavioral therapy (CBT) was superior to fibromyalgia (FM) education in reducing functional disability, pain, and symptoms of depression in juvenile FMS. METHODS: Participants were 114 adolescents (ages 11-18 years) with juvenile FMS. After receiving stable medications for 8 weeks, patients were randomized to either CBT or FM education and received 8 weekly individual sessions with a therapist and 2 booster sessions. Assessments were conducted at baseline, immediately following the 8-week treatment phase, and at 6-month followup. RESULTS: The majority of patients (87.7%) completed the trial per protocol. Intent-to-treat analyses showed that patients in both groups had significant reductions in functional disability, pain, and symptoms of depression at the end of the study, and CBT was significantly superior to FM education in reducing the primary outcome of functional disability (mean baseline to end-of-treatment difference between groups 5.39 [95% confidence interval 1.57, 9.22]). Reduction in symptoms of depression was clinically significant for both groups, with mean scores in the range of normal/nondepressed by the end of the study. Reduction in pain was not clinically significant for either group (<30% decrease in pain). There were no study-related adverse events. CONCLUSION: In this controlled trial, CBT was found to be a safe and effective treatment for reducing functional disability and symptoms of depression in adolescents with juvenile FMS.

Actigraphy-based physical activity monitoring in adolescents with juvenile primary fibromyalgia syndrome.

UNLABELLED: Juvenile primary fibromyalgia syndrome (JPFS) is a chronic pain condition associated with significant impairment in physical functioning, but no studies have used newer technologies such as actigraphy to document objective physical activity levels in JPFS. This is the first study to objectively describe physical activity in JPFS patients and examine the relationship of pain, perceived functional impairment, and depressive symptoms on physical activity. One hundred four clinically referred adolescents with JPFS (ages 11 to 18 years) wore a hip-mounted actigraph for 1 week. Data on pain intensity, functional disability, depressive symptoms, and psychiatric diagnoses were obtained using self- and parent-report measures and a standardized psychiatric interview. Results showed that younger patients were more active. Pain intensity was not significantly associated with physical activity levels overall, but the most highly active group of adolescents reported lower levels of pain and disability than the least active. Parent report of adolescents' physical functioning and depressive symptoms were significantly correlated with adolescents' physical activity levels. Actigraphy provides a unique source of information about physical functioning which is distinct from adolescents' self-report of physical functioning in JPFS. Preliminary findings suggest that further study of factors that predict perceived and actual physical functioning in JPFS is warranted. PERSPECTIVE: This study presents the results of physical activity monitoring in adolescents with JPFS using actigraphy. Results indicate that actigraphy provides a unique source of objective information that can advance our understanding of physical disability in JPFS and the factors associated with physical impairment.

Chronic constipation, atypical eating pattern, weight loss, and anxiety in a 19-year old youth.

CASE: A 19-year-old female was admitted to a children's hospital weighing 75 pounds. She lost 75 pounds over 2 years and did not menstruate for a year. Despite her dissatisfaction with her thin appearance and desire to weigh more, her inpatient treatment focused on "disordered eating." Adolescent medicine, nutrition, and gastroenterology specialists were consulted. A pediatric psychology consultation was initiated to address anxiety associated with eating as well as abnormal toileting behaviors. The patient reported that she had chronic constipation since the age 3 years with a large, hard, and painful bowel movement once every 1-3 weeks. She had numerous medical and nutritional interventions to improve her bowel functioning, including extensive laxative use and a diet high in fiber (mostly fruits and vegetables). Additionally, an extensive medical evaluation to look for physiological causes for chronic constipation, including Hirschsprung's disease, was not diagnostic. The patient described purposeful stool withholding due to her concern over painful bowel movements. She also avoided peer activities because she did not want to use toilets outside her home. The patient acknowledged that her disordered eating stemmed largely from her toileting difficulties. She described altering her eating habits to avoid bowel movements (e.g., eating small meals, not eating at school) and anxious thoughts while defecating. Defecation anxiety was now affecting other areas of her life. For example, she frequently used copious amounts of toilet paper to ensure thorough cleaning. The patient's parents confirmed her need to thoroughly clean after toilet use, using "almost half a roll of toilet paper." They described other concerning "routines," including refusing to use towels after showering. She dried herself with a fan because of fear that her towel may be dirty. They indicated that during early adolescence, she frequently washed her face to prevent acne breakouts. According to parents, the patient followed doctors' instructions "as though they (were) gospel," deviating from suggestions only with extreme resistance.

Relationship between school absenteeism and depressive symptoms among adolescents with juvenile fibromyalgia.

OBJECTIVE: To describe school absences in adolescents with Juvenile Primary Fibromyalgia Syndrome (JPFS) and examine the relationship between school absenteeism, pain, psychiatric symptoms, and maternal pain history. METHODS: Adolescents with JPFS (N = 102; mean age 14.96 years) completed measures of pain and depressive symptoms, and completed a psychiatric interview. Parents provided information about the adolescents' school absences, type of schooling, and parental pain history. School attendance reports were obtained directly from schools. RESULTS: Over 12% of adolescents with JPFS were homeschooled. Those enrolled in regular school missed 2.9 days per month on average, with one-third of participants missing more than 3 days per month. Pain and maternal pain history were not related to school absenteeism. However, depressive symptoms were significantly associated with school absences. CONCLUSION: Many adolescents with JPFS experience difficulties with regular school attendance. Long-term risks associated with school absenteeism and the importance of addressing psychological factors are discussed.

Anxiety, mood, and behavioral disorders among pediatric patients with juvenile fibromyalgia syndrome.

BACKGROUND: Mood and anxiety disorders are common psychiatric conditions among adult patients with fibromyalgia syndrome, but little is known about whether psychiatric disorders are prevalent among pediatric patients with fibromyalgia. OBJECTIVE: The primary objective of this study was to assess the prevalence of mood, anxiety, and behavioral disorders in a clinical sample of children and adolescents with juvenile primary fibromyalgia syndrome (JPFS) and assess the relationship between psychiatric disorders and JPFS symptom severity. METHODS: Standardized psychiatric interviews were conducted with children and their parents/primary caregivers, and measures of symptom severity including pain intensity and physician global ratings were obtained for 76 children and adolescents diagnosed with JPFS (ages 11 to 18 y) in pediatric rheumatology clinics at 4 hospitals in the Midwest. RESULTS: A total of 67.1% of patients had at least 1 current and 71.5% had at least 1 lifetime DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-fourth edition) psychiatric diagnosis. The most frequent psychiatric diagnosis was anxiety disorder (57.5% of JPFS patients). Although mood difficulties were also common, the presence of major depression was lower than has been reported for adults with fibromyalgia syndrome. Physicians' global assessment of functioning was significantly lower for patients with a current anxiety disorder. There were no significant differences in pain severity among patients with and without anxiety, mood, or behavioral disorders. DISCUSSION: There seems to be a high prevalence of anxiety disorders in patients with JPFS, and presence of anxiety disorder is associated with poorer physician-rated functioning. Future research should explore whether early anxiety symptoms are predictive of long-term functioning.

Repressive adaptation in a nonclinical sample: consistent and inconsistent reports of child psychosocial functioning across informants.

Using multiple indicators (self-report, parent report, school grades, and disciplinary referrals), we compared the psychosocial functioning of children across Weinberger's (1990) and Weinberger, Schwartz, and Davidson's (1979) repressive adaptive style (RAS) groups. Participants included 134 children ages 10 to 13 years that were recruited from public schools and 117 of their caregivers. Relative to nonrepressors, we hypothesized repressors to evidence lower levels of self-reported distress but higher parent-reported distress on the Behavior Assessment System for Children (BASC; Reynolds & Kamphaus, 1992). Summary scores from the BASC self-report differed significantly between repressors and nonrepressors in the expected directions. No significant group differences in parent-reported distress or school functioning emerged. Consistent with Phipps (2005), results question the predominant assumption that the RAS is associated with risk of psychosocial difficulties in children.

Children's self-reported coping strategies: the role of defensiveness and repressive adaptation.

This study examined differences in self-reported coping strategies across children classified according to Weinberger et al.'s (1979) adaptive style paradigm. Consistent with the larger literature, it was hypothesized that repressors (i.e. characterized by high self-reported defensiveness and low self-reported distress) would endorse fewer behaviorally and cognitively avoidant coping strategies than other adaptive style groups. Participants included 134 children, ranging in age from 10 to 13 (M=11.26, sd=.59), who completed measures of defensiveness, trait anxiety, and coping. Consistent with the hypotheses, results indicated significantly lower endorsement of avoidant coping strategies, and significantly higher endorsement of approach-oriented strategies among repressors, but no significant differences across adaptive style groups for other forms of coping. Results indicate that, consistent with other indicators of psychological functioning, the measurement of coping strategies is subject to the effects of socially desirable responding. Further, results provide evidence that measures of coping may be contaminated by items reflecting adjustment problems.

Time reproduction in finger tapping tasks by children with attention-deficit hyperactivity disorder and/or dyslexia.

AIM: Deficits in timing and sequencing behaviour in children with dyslexia and with attention-deficit hyperactivity disorder have already been identified. However many studies have not controlled for comorbidity between dyslexia and ADHD. This study investigated timing performance of children with either dyslexia or ADHD, or ADHD + dyslexia or unaffected children using a finger tapping paradigm. METHOD: Four groups of children (ADHD x Dyslexia) with a total of 68 children were compared using a four factorial design with two between-subject factors (ADHD (yes/no), dyslexia (yes/no)) and two within-subject factors, inter-stimulus interval (263, 500, 625, 750, 875 and 1000 ms) and tapping condition (free tapping, synchronous tapping, and unpaced tapping). In addition the complexity of rhythm reproduction pattern (unpaced tapping) was varied (simple/complex). RESULTS: No significant differences were found either in the ability of the ADHD or the dyslexia groups to sustain a self-chosen free tapping rate or to generate a stable inter-response interval either by synchronising to a signal or in reproducing a given interval without the previous pacing signal. Response averages showed the expected asynchrony and variability. In rhythm pattern reproduction the groups did not differ significantly in their ability to reproduce rhythms. However, a significant two way interaction effect between dyslexia and complexity was apparent indicating that the difference in levels of performance for simple versus complex rhythms was more pronounced for dyslexia than for the two other groups. CONCLUSION: The results indicate that motor timing ability in the millisecond range below 1000 ms in children with ADHD and/or dyslexia is intact. The performance of the comorbid group was revealed to be similar to the performance of the single disorder groups, but both the dyslexic groups were relatively worse than either the ADHD-only or the unimpaired group at reproducing complex versus simple rhythms.

Does disease management improve clinical and economic outcomes in patients with chronic diseases? A systematic review.

PURPOSE: To assess the clinical and economic effects of disease management in patients with chronic diseases. METHODS: Electronic databases were searched for English-language articles from 1987 to 2001. Articles were included if they used a systematic approach to care and evaluated patients with chronic disease, reported objective measurements of the processes or outcomes of care, and employed acceptable experimental or quasi-experimental study designs as defined by the Cochrane Effective Practice and Organization of Care Group. RESULTS: Two reviewers evaluated 16,917 titles and identified 102 studies that met the inclusion criteria. Identified studies represented 11 chronic conditions: depression, diabetes, rheumatoid arthritis, chronic pain, coronary artery disease, asthma, heart failure, back pain, chronic obstructive pulmonary disease, hypertension, and hyperlipidemia. Disease management programs for patients with depression had the highest percentage of comparisons (48% [41/86]) showing substantial improvements in patient care, whereas programs for patients with chronic obstructive pulmonary disease (9% [2/22]) or chronic pain (8% [1/12]) appeared to be the least effective. Of the outcomes more frequently studied, disease management appeared to improve patient satisfaction (71% [12/17]), patient adherence (47% [17/36]), and disease control (45% [33/74]) most commonly and cost-related outcomes least frequently (11% to 16%). CONCLUSION: Disease management programs were associated with marked improvements in many different processes and outcomes of care. Few studies demonstrated a notable reduction in costs. Further research is needed to understand how disease management can most effectively improve the quality and cost of care for patients with chronic diseases.

Physician attitudes toward strategies to promote the adoption of medical evidence into clinical practice.

BACKGROUND: [corrected] Promoting the adoption of medical evidence into clinical practice has been advocated as one approach to improving healthcare quality and reducing medical errors. Data describing the effectiveness of different strategies to achieve this goal in real-world settings are limited. OBJECTIVE: To determine the effectiveness of selected interventions on the adoption of medical evidence into clinical practice. STUDY DESIGN: A cross-sectional survey of a random sample of physicians selected from the American Medical Association's Physician Master File. PATIENTS AND METHODS: We examined the perceived effectiveness of 7 strategies (represented by 27 individual interventions) and 5 general approaches for promoting the adoption of medical evidence into clinical practice in 1100 practicing physicians. Respondent exposure to interventions was also determined. Regression analyses were performed to identify factors that affected effectiveness ratings. Analysis of variance was used to test the hypothesis of equal mean scores across different comparison groups. RESULTS: Of 1,100 surveys mailed, 63 (5.7%) were excluded and 431 were completed (response rate = 41.6%). Mean +/- SD effectiveness scores for the 27 individual interventions on a 5-point Likert scale ranged from 2.0 +/- 0.9 (literature received from insurance companies and managed care organizations) to 4.2 +/- 0.8 (one-on-one communication with respected colleagues). Ranges for the 7 strategies were 2.6 +/- 1.0 (patient-mediated interventions) to 3.6 +/- 0.9 (educational meetings) and for the 5 general approaches were 1.98 +/- 0.9 (administrative interventions) to 3.3 +/- 0.8 (provider education). The hypothesis of equal mean effectiveness scores was rejected for all comparisons (P < .001). Frequency of exposure was the only variable to predict effectiveness (P < .001 for all regression models). CONCLUSION: From the perspective of practicing physicians, the frequency of exposure to strategies for promoting the adoption of medical evidence into clinical practice strongly affects their perceived effectiveness.

Transforming the public health information infrastructure.

The public health information infrastructure is undergoing a transformation that is enabled by changes in health care informatics. The implementation of the Health Insurance Portability and Accountability Act (HIPAA) of 1996, the patient medical record information standards, and National Health Information Infrastructure (NHII) recommendations by the National Committee on Vital and Health Statistics provide the basis for improved data reporting to public health agencies. The U.S. Department of Health and Human Services should provide leadership and resources for this transformation. Newly available federal resources will have the greatest effect on improving the information infrastructure if there is a strong commitment to developing and implementing public health data standards that build upon the National Electronic Disease Surveillance System.

The limited incorporation of economic analyses in clinical practice guidelines.

BACKGROUND: Because there is increasing concern that economic data are not used in the clinical guideline development process, our objective was to evaluate the extent to which economic analyses are incorporated in guideline development. METHODS: We searched medline and HealthSTAR databases to identify English-language clinical practice guidelines (1996-1999) and economic analyses (1990-1998). Additional guidelines were obtained from The National Guidelines Clearinghouse Internet site available at http://www.guideline.gov. Eligible guidelines met the Institute of Medicine definition and addressed a topic included in an economic analysis. Eligible economic analyses assessed interventions addressed in a guideline and predated the guideline by 1 or more years. Economic analyses were defined as incorporated in guideline development if 1) the economic analysis or the results were mentioned in the text or 2) listed as a reference. The quality of economic analyses was assessed using a structured scoring system. RESULTS: Using guidelines as the unit of analysis, 9 of 35 (26%) incorporated at least 1 economic analysis of above-average quality in the text and 11 of 35 (31%) incorporated at least 1 in the references. Using economic analyses as the unit of analysis, 63 economic analyses of above-average quality had opportunities for incorporation in 198 instances across the 35 guidelines. Economic analyses were incorporated in the text in 13 of 198 instances (7%) and in the references in 18 of 198 instances (9%). CONCLUSIONS: Rigorous economic analyses may be infrequently incorporated in the development of clinical practice guidelines. A systematic approach to guideline development should be used to ensure the consideration of economic analyses so that recommendations from guidelines may impact both the quality of care and the efficient allocation of resources.