Challenges and visions for managing pain-related insomnia in primary care using the hybrid CBT approach: a small-scale qualitative interview study with GPs, nurses, and practice managers.

BACKGROUND: Chronic pain and insomnia have a complex, bidirectional relationship - addressing sleep complaints alongside pain may be key to alleviating patient-reported distress and disability. Healthcare professionals have consistently reported wanting to offer psychologically informed chronic pain management at the primary care level. Research in secondary care has demonstrated good treatment efficacy of hybrid CBT for chronic pain and insomnia. However, primary care is typically the main point of treatment entry, hence may be better situated to offer treatments using a multidisciplinary approach. In this study, primary care service providers' perception of feasibility for tackling pain-related insomnia in primary care was explored. METHODS: The data corpus originates from a feasibility trial exploring hybrid CBT for chronic pain and insomnia delivered in primary care. This formed three in-depth group interviews with primary care staff (n = 9) from different primary care centres from the same NHS locale. All interviews were conducted on-site using a semi-structured approach. Verbal data was recorded, transcribed verbatim and analysed using the thematic analysis process. RESULTS: Eight themes were identified - 1) Discrepant conceptualisations of the chronic pain-insomnia relationship and clinical application, 2) Mismatch between patients' needs and available treatment offerings, 3) Awareness of psychological complexities, 4) Identified treatment gap for pain-related insomnia, 5) Lack of funding and existing infrastructure for new service development, 6) General shortage of psychological services for complex health conditions, 7) Multidisciplinary team provision with pain specialist input, and 8) Accessibility through primary care. These mapped onto four domains - Current understanding and practice, Perceived facilitators, Perceived barriers, Ideal scenarios for a new treatment service - which reflected the focus of our investigation. Taken together these provide key context for understanding challenges faced by health care professionals in considering and developing a new clinical service. CONCLUSIONS: Primary care service providers from one locale advocate better, multidisciplinary treatment provision for chronic pain and insomnia. Findings suggest that situating this in primary care could be a feasible option, but this requires systemic support and specialist input as well as definitive trials for success.

Robust singlet fission in pentacene thin films with tuned charge transfer interactions.

Singlet fission, the spin-allowed photophysical process converting an excited singlet state into two triplet states, has attracted significant attention for device applications. Research so far has focused mainly on the understanding of singlet fission in pure materials, yet blends offer the promise of a controlled tuning of intermolecular interactions, impacting singlet fission efficiencies. Here we report a study of singlet fission in mixtures of pentacene with weakly interacting spacer molecules. Comparison of experimentally determined stationary optical properties and theoretical calculations indicates a reduction of charge-transfer interactions between pentacene molecules with increasing spacer molecule fraction. Theory predicts that the reduced interactions slow down singlet fission in these blends, but surprisingly we find that singlet fission occurs on a timescale comparable to that in pure crystalline pentacene. We explain the observed robustness of singlet fission in such mixed films by a mechanism of exciton diffusion to hot spots with closer intermolecular spacings.

A multicentred randomised controlled trial of a primary care-based cognitive behavioural programme for low back pain. The Back Skills Training (BeST) trial.

OBJECTIVES: To estimate the clinical effectiveness of active management (AM) in general practice versus AM plus a group-based, professionally led cognitive behavioural approach (CBA) for subacute and chronic low back pain (LBP) and to measure the cost of each strategy over a period of 12 months and estimate cost-effectiveness. DESIGN: Pragmatic multicentred randomised controlled trial with investigator-blinded assessment of outcomes. SETTING: Fifty-six general practices from seven English regions. PARTICIPANTS: People with subacute and chronic LBP who were experiencing symptoms that were at least moderately troublesome. INTERVENTIONS: Participants were randomised (in a ratio of 2:1) to receive either AM+CBA or AM alone. MAIN OUTCOME MEASURES: Primary outcomes were the Roland Morris Disability Questionnaire (RMQ) and the Modified Von Korff Scale (MVK), which measure LBP and disability. Secondary outcomes included mental and physical health-related quality of life (Short Form 12-item health survey), health status, fear avoidance beliefs and pain self-efficacy. Cost-utility of CBA was considered from both the UK NHS perspective and a broader health-care perspective, including both NHS costs and costs of privately purchased goods and services related to LBP. Quality-adjusted life-years (QALYs) were calculated from the five-item EuroQoL. RESULTS: Between April 2005 and April 2007, 701 participants were randomised: 233 to AM and 468 to AM+CBA. Of these, 420 were female. The mean age of participants was 54 years and mean baseline RMQ was 8.7. Outcome data were obtained for 85% of participants at 12 months. Benefits were seen across a range of outcome measures in favour of CBA with no evidence of group or therapist effects. CBA resulted in at least twice as much improvement as AM. Mean additional improvement in the CBA arm was 1.1 [95% confidence interval (CI) 0.4 to 1.7], 1.4 (95% CI 0.7 to 2.1) and 1.3 (95% CI 0.6 to 2.1) change points in the RMQ at 3, 6 and 12 months respectively. Additional improvement in MVK pain was 6.8 (95% CI 3.5 to 10.2), 8.0 (95% CI 4.3 to 11.7) and 7.0 (95% CI 3.2 to 10.7) points, and in MVK disability was 4.3 (95% CI 0.4 to 8.2), 8.1 (95% CI 4.1 to 12.0) and 8.4 (95% CI 4.4 to 12.4) points at 3, 6 and 12 months respectively. At 12 months, 60% of the AM+CBA arm and 31% of the AM arm reported some or complete recovery. Mean cost of attending a CBA course was 187 pounds per participant with an additional benefit in QALYs of 0.099 and an additional cost of 178.06 pounds. Incremental cost-effectiveness ratio was 1786.00 pounds. Probability of CBA being cost-effective reached 90% at about 3000 pounds and remained at that level or above; at a cost-effectiveness threshold of 20,000 pounds the CBA group had an almost 100% probability of being considered cost-effective. User perspectives on the acceptability of group treatments were sought through semi-structured interviews. Most were familiar with key messages of AM; most who had attended any group sessions had retained key messages from the sessions and two-thirds talked about a reduction in fear avoidance and changes in their behaviour. Group sessions appeared to provide reassurance, lessen isolation and enable participants to learn strategies from each other. CONCLUSIONS: Long-term effectiveness and cost-effectiveness of CBA in treating subacute and chronic LBP was shown, making this intervention attractive to patients, clinicians and purchasers. Short-term (3-month) clinical effects were similar to those found in high-quality studies of other therapies and benefits were maintained and increased over the long term (12 months). Cost per QALY was about half that of competing interventions for LBP and because the intervention can be delivered by existing NHS staff following brief training, the back skills training programme could be implemented within the NHS with relative ease. TRIAL REGISTRATION: Current Controlled Trials ISRCTN37807450. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Contribution of villous atrophy to reduced intestinal maltase in infants with malnutrition.

BACKGROUND: It has been known for many years that small intestinal maltase activities are reduced in malnourished infants and in other patients with villous atrophy. The recent availability of human maltase-glucoamylase cDNA provides the opportunity to test the hypothesis that villous atrophy accounts for the reduced maltase enzyme activity in malnourished infants. METHODS: Mucosal biopsy specimens obtained for clinical evaluation of malnourished infants with poor responses to refeeding were examined by quantitative methods for enzyme activity and mRNA levels. RESULTS: Maltase activity and maltase-glucoamylase mRNA were reduced (approximately 45% of normal). When maltase-glucoamylase message was normalized to villin message, a structural protein expressed only in enterocytes, a preservation of maltase messages in surviving enterocytes was documented. The luminal glucose transporter-villin message was also preserved. CONCLUSIONS: The loss of maltase-glucoamylase message paralleled the reduction in villin message and degree of villous atrophy. The reduced maltase-glucoamylase message also paralleled sucrase-isomaltase message, previously found to be decreased in proportion to villous atrophy of malnourished infants. The data directly demonstrate, for the first time, that the terminal steps of starch 1-4 starch digestion and sucrase-isomaltase 1-6 starch digestion are decreased in malnourished infants, secondary to villous atrophy. These data in prior and present reports suggest that mechanisms underlying the chronic villous atrophy of malnutrition should be a priority for investigations in malnourished infants with slower than expected weight gain during refeeding.

Effects of malnutrition on expression and activity of lactase in children.

BACKGROUND & AIMS: Many malnourished infants have reduced lactase specific activity in the small intestine. The aim of this study was to test the hypothesis that the hypolactasia of malnourished infants results from transcriptional suppression of lactase expression. METHODS: Biopsy specimens were studied from two groups of infants: 29 with malnutrition and 10 normally nourished controls with normal morphology and lactase activity. RESULTS: In malnourished infants, lactase messenger RNA (mRNA) was reduced to 32% and sucrase to 61% of normal. Lactase and sucrase enzyme proteins and activities were lower in malnourished infants, and partial villus atrophy was present. The genotype of adult hypolactasia was not present. CONCLUSIONS: Because the hypolactasia of malnourished children was associated with much lower lactase than sucrase mRNA abundance and because the epigenetic suppression, which accounted for the reduction of sucrase mRNA, was inadequate to explain the greater reduction of lactase mRNA, this study concludes that malnutrition suppresses lactase gene transcription or mRNA stability in infants. The reductions of lactase mRNA, distinct from those found in adults with genetic hypolactasia, explain the low lactase activities commonly found in malnourished infants.

Changes in insulin-like growth factor-I (IGF-I), IGF-binding protein-3, growth hormone (GH)-binding protein, erythrocyte IGF-I receptors, and growth rate during GH treatment.

To assess the relative determinants of growth rate, we measured serum levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and GH-binding protein (GHBP) as well as IGF-I erythrocyte receptor specific binding (SB) in 14 prepubertal GH-deficient children before and during the first year of treatment with 0.043 mg/kg.day GH. Serum IGF-I and IGFBP-3 levels, measured by RIA, were significantly increased by 2 weeks and showed progressive increases throughout the year of GH therapy. Growth rate (height velocity SD score adjusted for bone age) correlated best with the 12 month changes in IGFBP-3 (r = 0.81; P < 0.001) and IGF-I (r = 0.72; P = 0.005), and to a lesser extent with the 12 month absolute IGFBP-3 (r = 0.58; P = 0.04) and the 6 month change in IGFBP-3 (r = 0.55; P = 0.05). The baseline IGF-I correlated inversely with the growth rate during GH therapy (r = -0.55; P = 0.05) and was the best pretreatment predictor of growth response. GHBP, as measured by ligand-mediated immunofunctional assay, showed no significant change during GH therapy and did not correlate with growth response. The baseline GHBP, however, did correlate with both the 12 month IGFBP-3 (r = 0.72; P = 0.006) as well as the 2 week change in IGFBP-3 (r = 0.63; P = 0.05). Erythrocyte IGF-I SB showed a significant decrease by 6 months secondary to a decrease in IGF-I receptor number, with no change in affinity. The 6 month IGF-I receptor binding correlated inversely with the increase in IGF-I (r = -0.88; P < 0.001). Erythrocyte IGF-I SB at baseline did not correlate with the growth response, although there was an inverse trend between the 6 month IGF-I receptor level and the growth rate. IGF-I and IGFBP-3 show progressive increases, whereas the erythrocyte IGF-I receptor-binding capacity decreases by 6 months, and GHBP shows little change during the first year of GH treatment. Data from this study suggest that changes in IGFBP-3 and, to a lesser extent, IGF-I are the major correlates of growth rate, and that down-regulation of the IGF-I receptor may have relatively little influence on growth rate compared with changes in IGFBP-3 and IGF-I.

Volume of blood required to obtain central venous catheter blood cultures in infants and children.

To determine how much blood must be discarded before one can obtain a reliable central venous catheter blood culture, we prospectively cultured the blood (from 96 patients) that is ordinarily discarded before obtaining blood for such a culture. We then compared the prospective culture results with those of the actual blood culture. Three sequentially drawn aliquots of blood were aspirated from the central venous catheter and cultured. The culture results of the second aliquot were comparable to those of the third (the portion usually cultured) in overall sensitivity (94.4%), specificity (94.9%), and positive predictive value (80.9%). Thus, the amount of blood that must be discarded (infants: 0.3 mL; children: 1.0 mL) before one can obtain an accurate central venous catheter culture is less than was previously thought.

Mosaic expression of brush-border enzymes in infants with chronic diarrhea and malnutrition.

The chronic diarrhea observed in young malnourished infants that is sensitive to dietary glucose and other carbohydrates is associated with variable degrees of patchy mucosal villous atrophy. To explore intrinsic mucosal function in the pathogenesis of this alimentary intolerance, we have conducted an immunohistologic investigation of brush-border enzyme proteins of clinically obtained, mucosal biopsy samples. We used a group of monoclonal antibodies against human brush-border aminopeptidase, sucrase/isomaltase (SI), maltase, and lactase enzyme proteins. SI was strongly and uniformly expressed in crypts and villi of 11 of the 14 subjects; in 3 subjects, however, SI was expressed in a mosaic pattern. Maltase and lactase were occasionally absent, but more commonly were expressed in a mosaic distribution. The mosaic expression of brush-border enzyme proteins has been reported in congenital enzyme deficiencies associated with normal intestinal histology. We report the mosaic expression of brush-border enzyme proteins as a functional alteration associated with a pathological lesion of the mucosa in infants with chronic diarrhea. Our observation challenges the existing concept of ontogenic regulation of brush-border enzyme activity.

Pathogenesis of small-intestinal mucosal lesions in chronic diarrhea of infancy: I. A light microscopic study.

In an effort to increase our understanding of the pathogenesis of chronic protracted diarrhea in infants, we examined 44 jejunal mucosal specimens. Only 3 of the 44 specimens showed a normal mucosa (grade 1). Partial villous atrophy was seen in 17 mucosal specimens (grade 2) with marked patchiness in all of the specimens. Subtotal or total villous atrophy (grade 3) was found in the remaining 24 mucosal biopsies. Plasma cells and macrophages were variably increased and intraepithelial lymphocytes were moderately increased in grades 2 and 3. Eight of ten mucosal biopsy specimens embedded in plastic material and cut at 1-2-mm thickness, showed bacteria of unidentified nature, situated either above the microvillous layer or on the mucosal surface. Both adherent and nonadherent bacteria could be identified in the same specimen. We concluded that severe pathological mucosal changes are common in young infants with protracted diarrhea and that the presence of bacteria may be more common than has previously been documented.

Pathogenesis of small-intestinal mucosal lesions in chronic diarrhea of infancy: II. An electron microscopic study.

Our electron microscopic study of biopsies taken from 10 infants with protracted diarrhea was conducted in an effort to determine the pathogenesis of the disorder. In this article, the ultrastructure of the jejunal mucosa of the infants is described in relation to overlying or adherent bacteria of unidentified type. In addition to the known changes on the enterocyte surface caused by adherent bacteria (cupping and effacement), other cytopathic changes, not previously reported, are documented. Included are widespread loss of enterocytes, including intraepithelial lymphocytes, into the bowel lumen; cytopathological changes within the enterocytes; and marked thickening of the basal laminae of the enterocytes and the endothelium of lamina propria blood vessels. In addition, we noted deposition of collagen fibrils in the lamina propria below the basal laminae, active phagolysis within macrophages, and lack of cisternal material (immunoglobulin) in the plasma-cell cytoplasm. Although these changes are nonspecific, they may be related in part to the presence of the nonadhering and adhering bacteria, and their identification may further our understanding of the "sick mucosa" that occurs in chronic diarrhea of infancy.

Dietary origin of retained H+ in infants with acquired monosaccharide intolerance.

Net external acid balance was studied in 12 malnourished infants with chronic diarrhea (some of whom had acquired monosaccharide intolerance). When the infants achieved an adequate energy intake from a formula that contained either glucose or glucose polymers, seven developed metabolic acidosis and five remained free of acidosis. During the study, the acidotic infants produced a significant excess of acid (3.7 +/- 2 vs. 0.5 +/- 2 mEq/kg/day, p less than 0.005). The amount they excreted in urine (2.9 +/- 2 mEq/kg/day), however, was similar to that excreted by nonacidotic infants (2.7 +/- 2 mEq/kg/day) and indicated renal inability to reduce the excess acid load. The net effect was hydrogen ion (H+) retention (+0.8 +/- 0.8 vs. -2.2 +/- 0.8 mEq/kg/day, p less than 0.001). Good correlation existed between the net acid balance and the acid-base measurement in the blood. We speculate that (a) the increased acid load was a consequence of colonic bacterial production of volatile fatty acids from carbohydrate malabsorbed from the small bowel and (b) the renal incapacity to excrete H+ probably was secondary to potassium and phosphate depletion.

Human lactoferrin supplementation of infant formulas increases thymidine incorporation into the DNA of rat crypt cells.

Lactoferrin has been identified as the factor in human colostrum that accounts for the increased incorporation of thymidine into DNA in a rat crypt enterocyte bioassay. Commercially available infant formulas used in the refeeding of infants who have severe dietary intolerance associated with mucosal atrophy were tested in this bioassay. In contrast to human milk, no stimulation was observed with these formulas in the assay. All formulas inhibited basal thymidine incorporation. The degree of inhibition of the basal assay progressed from 14% with cow's-milk formula to 30% with soy-based formulas to 45% with hydrolyzed casein formulas. When the formulas were supplemented with lactoferrin to match the level of that in human milk, the result was a 35% relative increase in thymidine incorporation into DNA. The quantitative level of response was primarily influenced by the baseline inhibitions associated with the specific formulas. The most profound effect was observed with the hydrolyzed casein formula, when lactoferrin supplementation reversed the baseline inhibition but did not result in a response greater than that seen in control basal bioassays. The supplementation of infant formulas with lactoferrin improved the thymidine incorporation in rat crypt enterocytes; a response equivalent to that of human milk, however, would require a redesign of other formula components to reduce basal inhibition.

Acquired monosaccharide intolerance in infants.

To determine the frequency with which acquired monosaccharide intolerance (AMI) occurs in infants less than 3 months of age, we performed a prospective descriptive study of infants admitted to the hospital for diarrhea. We searched for differences between the characteristics and causes of AMI in these infants and those of a cohort of similar-aged infants admitted with acute diarrhea (AD). Five hundred fifty-five infants less than 3 months of age admitted with diarrhea were enrolled. Nine percent of those infants had AMI, 40% had other forms of chronic diarrhea, and 51% had AD. The mean age at hospital admission was 32 days for the infants with AMI and 44 days for the infants with AD. The mean weight loss of AMI infants was 0.3 g/day since birth, and the mean weight gain was 14.3 g/day for AD infants. The mean dehydration by difference in weights at admission and 48 h postadmission was 5% for AMI and 3% for AD infants. Bacterial and viral causes of the diarrhea were similar. At admission to the hospital, infants in whom AMI subsequently developed were younger, more malnourished, had more prolonged diarrhea, and were more dehydrated than the AD infants. Malnutrition stands out as a significant antecedent factor that contributes to the development of AMI.

Malnutrition in infants with acute diarrheal syndrome.

The data from the charts of 109 infants who were younger than 9 months of age and who had been hospitalized with acute diarrheal syndrome in 1978 were compared with data from the charts of 108 healthy infants of the same age range with the same sex and ethnic distributions who were attending well-child clinics serving the same geographic area during the same year. In a comparison of weight percentiles, 45.3% of the acute diarrheal syndrome patients and 11.3% of the well children were below the 10th percentile. When height percentiles were compared, 41.8% of the acute diarrheal syndrome patients and 15.3% of the well children were below the 10th percentile. The data indicate that malnutrition was a characteristic of infants with acute diarrheal syndrome who required hospitalization.

Comparison of acquired monosaccharide intolerance and acute diarrheal syndrome.

In a retrospective study, 9% of the admissions to Ben Taub General Hospital for diarrhea were found to have acquired monosaccharide intolerance (AMI). The course of AMI was compared with that of acute diarrheal syndrome (ADS). The patients with AMI were younger at the time of admission, and, although the mean birthweight and percent of prematurity were approximately the same in the two groups, the AMI patients were found to be malnourished (p less than 0.02). Data suggest that the nutritional insult had occurred between birth and admission, and that malnutrition was a contributing factor in the development of AMI.