Counting your chickens before they hatch: improvements in an untreated chronic pain population, beyond regression to the mean and the placebo effect.

Introduction: Isolating the effect of an intervention from the natural course and fluctuations of a condition is a challenge in any clinical trial, particularly in the field of pain. Regression to the mean (RTM) may explain some of these observed fluctuations. Objectives: In this paper, we describe and quantify the natural trajectory of questionnaire scores over time, based on initial scores. Methods: Twenty-seven untreated chronic low back pain patients and 25 healthy controls took part in this observational study, wherein they were asked to complete an array of questionnaires commonly used in pain studies during each of 3 visits (V1, V2, V3) at the 2-month interval. Scores at V1 were classified into 3 subgroups (extremely high, normal, and extremely low), based on z-scores. The average delta (∆ = V2 - V1) was calculated for each subgroup, for each questionnaire, to describe the evolution of scores over time based on initial scores. This analysis was repeated with the data for V2 and V3. Results: Our results show that high initial scores were widely followed by more average scores, while low initial scores tended to be followed by similar (low) scores. Conclusion: These trajectories cannot be attributable to RTM alone because of their asymmetry, nor to the placebo effect as they occurred in the absence of any intervention. However, they could be the result of an Effect of Care, wherein participants had meaningful improvements simply from taking part in a study. The improvement observed in patients with high initial scores should be carefully taken into account when interpreting results from clinical trials.

Value of Nutrition Support Therapy: Impact on Clinical and Economic Outcomes in the United States.

OBJECTIVE: Healthcare leaders seek guidance on prudent investment in programs that improve patient outcomes and reduce costs, which includes the value of nutrition therapy. The purpose of this project was to conduct an evidence review and evaluate claims analyses to understand the financial and quality impact of nutrition support therapy on high-priority therapeutic conditions. METHODS: Task 1 included a review of existing literature from 2013 to 2018 to identify evidence that demonstrated the clinical and economic impact of nutrition intervention on patient outcomes across 13 therapeutic areas (TAs). In Task 2, analytic claims modeling was performed using the Medicare Parts A and B claims 5% sample dataset. Beneficiaries diagnosed in 5 selected TAs (sepsis, gastrointestinal [GI] cancer, hospital-acquired infections, surgical complications, and pancreatitis) were identified in the studies from Task 1, and their care costs were modeled based on nutrition intervention. RESULTS: Beginning with 1099 identified articles, 43 articles met the criteria, with a final 8 articles used for the Medicare claims modeling. As examples of the modeling demonstrated, the use of advanced enteral nutrition formula could save at least $52 million annually in a sepsis population. The total projected annual cost savings from the 5 TAs was $580 million. CONCLUSION: Overall, optimization of nutrition support therapy for specific patient populations is estimated to reduce Medicare spending by millions of dollars per year across key TAs. These findings demonstrate the evidence-based value proposition of timely nutrition support to improve clinical outcomes and yield substantial cost savings.

Hospital Inpatient Admissions With Dehydration and/or Malnutrition in Medicare Beneficiaries Receiving Enteral Nutrition: A Cohort Study.

BACKGROUND: Enteral nutrition (EN) supports many older and disabled Americans. This study describes the frequency and cost of acute care hospitalization with dehydration and/or malnutrition of Medicare beneficiaries receiving EN, focusing on those receiving home EN. METHODS: Medicare 5% Standard Analytic Files were used to determine Medicare spending for EN supplies and the proportion and cost of beneficiaries receiving EN, specifically home EN, admitted to the hospital with dehydration and/or malnutrition. RESULTS: In 2013, Medicare paid $370,549,760 to provide EN supplies for 125,440 beneficiaries, 55% of whom were also eligible for Medicaid. Acute care hospitalization with dehydration and/or malnutrition occurred in 43,180 beneficiaries receiving EN. The most common principal diagnoses were septicemia (21%), aspiration pneumonitis (9%), and pneumonia (5%). In beneficiaries receiving EN at home, >one-third (37%) were admitted with dehydration and/or malnutrition during a mean observation interval of 231 ± 187 days. Admitted patients were usually hospitalized more than once with dehydration and/or malnutrition (1.73 ± 1.30 admissions) costing $23,579 ± 24,966 per admitted patient, totaling >$129,685,622 during a mean observation interval of 276 ± 187 days. Mortality in the year following enterostomy tube placement was significantly higher for admitted compared with nonadmitted patients (40% vs 33%; P = .05). CONCLUSION: Acute care hospitalizations with dehydration and/or malnutrition in Medicare beneficiaries receiving EN were common and expensive. Additional strategies to reduce these, with particular focus on vulnerable populations such as Medicaid-eligible patients, are needed.

Identification of the Salmonella enterica serotype typhimurium SipA domain responsible for inducing neutrophil recruitment across the intestinal epithelium.

In human intestinal disease induced by Salmonella enterica serotype Typhimurium (S. typhimurium) transepithelial migration of polymorphonuclear leukocytes (PMNs) rapidly follows attachment of the bacteria to the epithelial apical membrane. Previously, we have shown that the S. typhimurium effector protein, SipA, plays a pivotal role in signalling epithelial cell responses that lead to the transepithelial migration of PMNs. Thus, the objective of this study was to determine the functional domain of SipA that regulates this signalling event. SipA was divided into two fragments: the SipAb C-terminal fragment(426-684) (259 AA), which binds actin, and the SipAa fragment(2-425) (424 AA), which a role has yet to be described. In both in vitro and in vivo models of S. typhimurium-induced intestinal inflammation the SipAa fragment exhibited a profound ability to induce PMN transmigration, whereas the SipAb actin-binding domain failed to induce PMN transmigration. Subsequent mapping of the SipAa domain identified a 131-amino-acid region (SipAa3(294-424)) responsible for modulating PMN transepithelial migration. Interestingly, neither intracellular translocation nor actin association of SipA was necessary for its ability to induce PMN transepithelial migration. As these results indicate SipA has at least two separate functional domains, we speculate that during infection S. typhimurium requires delivery of SipA to both extracellular and intracellular spaces to maximize pro-inflammatory responses and mechanisms of bacterial invasion.

Salmonella typhimurium SipA-induced neutrophil transepithelial migration: involvement of a PKC-alpha-dependent signal transduction pathway.

Salmonella typhimurium elicits an intense proinflammatory response characterized by movement of polymorphonuclear neutrophils (PMN) across the epithelial barrier to the intestinal lumen. We previously showed that S. typhimurium, via the type III secretion system effector protein SipA, initiates an ADP-ribosylation factor-6- and phospholipase D-dependent lipid-signaling cascade that directs activation of protein kinase C (PKC) and subsequent transepithelial movement of PMN. Here we sought to determine the specific PKC isoforms that are induced by the S. typhimurium effector SipA in model intestinal epithelia and to link the functional consequences of these isoforms in the promotion of PMN transepithelial migration. In vitro kinase PKC activation assays performed on polarized monolayers of T84 cells revealed that S. typhimurium and recombinant SipA induced activation of PKC-alpha, -delta, and -epsilon. To elucidate which of these isoforms play a key role in mediating epithelial cell responses that lead to the observed PMN transepithelial migration, we used a variety of PKC inhibitors with different isoform selectivity profiles. Inhibitors selective for PKC-alpha (Gö-6976 and 2,2',3,3',4,4'-hexahydroxyl-1,1'-biphenyl-6,6'-dimethanoldimethyl ether) markedly reduced S. typhimurium- and recombinant SipA-induced PMN transepithelial migration, whereas inhibitors to PKC-delta (rottlerin) or PKC-epsilon (V1-2) failed to exhibit a significant decrease in transepithelial movement of PMN. These results were confirmed biochemically and by immunofluorescence coupled to confocal microscopy. Our results are the first to show that the S. typhimurium effector protein SipA can activate multiple PKC isoforms, but only PKC-alpha is involved in the signal transduction cascade leading to PMN transepithelial migration.

CARD15/NOD2 functions as an antibacterial factor in human intestinal epithelial cells.

BACKGROUND & AIMS: Mutations in the CARD15/NOD2 gene, a putative intracellular pattern recognition receptor, have been linked to the risk for Crohn's disease. Because intestinal epithelial cells play a role as the barrier to luminal microorganisms, we investigated the expression and function of CARD15/NOD2 in intestinal epithelial cells. METHODS: Expression of CARD15/NOD2 messenger RNA (mRNA) in intestinal epithelial cell lines and primary intestinal epithelial cells was assessed by reverse-transcription polymerase chain reaction (RT-PCR). Regulation of expression of CARD15/NOD2 by cytokines was determined by Northern blot using the SW480 cell line. Active CARD15/NOD2 protein in SW480 cells was assessed by the combination of immunoprecipitation and immunoblotting using anti-CARD15/NOD2 antisera. To identify the functional role of CARD15/NOD2 in intestinal epithelial cells, gentamicin protection assays of Salmonella typhimurium were performed using Caco2 cells stably transfected with either wild-type CARD15/NOD2 or the 3020insC mutant associated with Crohn's disease. RESULTS: CARD15/NOD2 mRNA was expressed in both intestinal epithelial cell lines and primary intestinal epithelial cells. CARD15/NOD2 mRNA and protein were up-regulated by tumor necrosis factor alpha (TNFalpha) in SW480 cells. The number of viable internalized S. typhimurium in Caco2 cells stably transfected with CARD15/NOD2 expression plasmid was lower than untransfected Caco2 cells or MOCK transfectant. In contrast, expression of a variant associated with Crohn's disease was unable to constrain bacterial survival. CONCLUSIONS: CARD15/NOD2 is expressed in intestinal epithelial cells and may serve as a key component of innate mucosal responses to luminal bacteria as an antibacterial factor. Failure in this activity may contribute to the development of Crohn's disease.

Polymorphonuclear leukocyte migration across model intestinal epithelia enhances Salmonella typhimurium killing via the epithelial derived cytokine, IL-6.

The host response to Salmonella typhimurium involves movement of polymorphonuclear leukocytes (PMN) across the epithelium and into the intestinal lumen. Following their arrival in the lumen, the PMN attempt to combat bacterial infection by activating antimicrobial defenses such as granule release, oxidative burst, phagocytosis, and cell signaling. We sought to examine PMN-S. typhimurium interaction following PMN arrival in the lumenal compartment. Here, for the first time, we demonstrate that PMN that have transmigrated across model intestinal epithelia have an enhanced ability to kill S. typhimurium. Our data provide evidence to indicate that the extracellular release of the primary and secondary granules of PMN, myeloperoxidase and lactoferrin, respectively, is correlated with enhanced bacterial killing. Furthermore, epithelial cells, during PMN transmigration, release the cytokine IL-6. IL-6 is known to increase intracellular stores of Ca(2+), and we have determined that this epithelial released cytokine is not only responsible for priming the PMN to release their granules, but also stimulating the PMN to kill S. typhimurium. These results substantiate the pathway in which PMN transmigration activates the epithelial release of IL-6, which in turn increases intracellular Ca(2+) storage. Our results, herein, extend this pathway to include an enhanced PMN granule release and an enhanced killing of S. typhimurium.