Trimming the fat: is there a health economic case for the use of new lipid-lowering drugs in chronic kidney disease? A scoping review.

Background: Individuals with chronic kidney disease (CKD) are at a very high risk for atherosclerotic cardiovascular disease (ASCVD). New lipid-lowering agents offer hope of improved outcomes where traditional agents have been less efficacious, yet the cost of these agents needs consideration in this population before their widespread application. Objective: We sought to evaluate the cost-effectiveness of novel lipid-lowering therapies for a CKD population. Methods: We searched four electronic databases, one government registry and the reference lists of included literature to identify cost-effectiveness analyses of novel lipid-lowering agents in CKD. Costs were converted to a single currency to allow cross-country comparisons. Completeness of reporting was analysed using the Consolidated Health Economic Evaluation Reporting Standards checklist. Results were synthesized in narrative form with graphical representation of cost-effectiveness ratios. Results: Of the 1041 identified studies, 4 met the inclusion criteria. None were specific to a CKD-only population. All examined the impact of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) in the secondary prevention of ASCVD. Incremental cost-effectiveness ratios of new agents compared with standard care were between €7288 and €112 530 per quality-adjusted life year gained. Cost-effectiveness was sensitive to the degree of cardiovascular risk of the underlying populations. Conclusion: This review found PCSK9is were moderately cost-effective in populations with high cardiovascular risk. People with CKD were included as an undifferentiated subpopulation in the primary studies, but application of these findings to CKD-specific populations should be interpreted with caution. There is insufficient evidence for a health economic case to support novel lipid-lowering therapies for advanced CKD.

Stem Cell Marker Expression in Early Stage Colorectal Cancer is Associated with Recurrent Intestinal Neoplasia.

BACKGROUND: Colorectal cancer (CRC) ranks second in cancer deaths worldwide and presents multiple management challenges, one of which is identifying high risk stage II disease that may benefit from adjuvant therapy. Molecular biomarkers, such as ones that identify stem cell activity, could better stratify high-risk cohorts for additional treatment. METHODS: To identify possible biomarkers of high-risk disease in early-stage CRC, a discovery set (n = 66) of advanced-stage tumors were immunostained with antibodies to stemness proteins (CD166, CD44, CD26, and LGR5) and then digitally analyzed. Using a second validation cohort (n = 54) of primary CRC tumors, we analyzed protein and gene expression of CD166 across disease stages, and extended our analyses to CD166-associated genes (LGR5, ASCL2, BMI1, POSTN, and VIM) by qRT-PCR. RESULTS: Stage III and metastatic CRC tumors highly expressed stem cell-associated proteins, CD166, CD44, and LGR5. When evaluated across stages, CD166 protein expression was elevated in advanced-stage compared to early-stage tumors. Notably, a small subset of stage I and II cancers harbored elevated CD166 protein expression, which correlated with development of recurrent cancer or adenomatous polyps. Gene expression analyses of CD166-associated molecules revealed elevated ASCL2 in primary tumors from patients who recurred. CONCLUSIONS: We identified a protein signature prognostic of aggressive disease in early stage CRC. Stem cell-associated protein and gene expression identified a subset of early-stage tumors associated with cancer recurrence and/or subsequent adenoma formation. Signatures for stemness offer promising fingerprints for stratifying early-stage patients at high risk of recurrence.

Cost-Effectiveness of Continuous Support From a Layperson During a Woman's First Two Births.

OBJECTIVE: To evaluate the cost-effectiveness and health outcomes related to continuous support from a layperson during a woman's first two births in a theoretical population. DESIGN: Cost-effectiveness analysis. PARTICIPANTS: A theoretical cohort of 1.2 million women based on an approximation of annual low-risk, nulliparous, term, singleton births in the United States with the assumption that these women have second births. This reflects the average number of births per woman in the United States. METHODS: We designed a cost-effectiveness model to compare outcomes in women with continuous support from relatives, friends, or community members with minimal to no training (excluding trained doulas) during labor and birth compared with outcomes for women with no continuous support. Outcomes included mode of birth, uterine rupture, hysterectomy, maternal death, cost, and quality-adjusted life years (QALYs). We derived probabilities from the literature and set a cost-effectiveness threshold at $100,000/QALY. RESULTS: In this theoretical model, continuous support by a layperson during the first birth resulted in fewer cesarean births, decreased costs, and increased QALYs for the first and subsequent births. Women with support from laypersons had 71,090 fewer cesarean births, 35 fewer uterine ruptures, 9 fewer hysterectomies, and 16 fewer maternal deaths, which saved $364 million with 2,673 increased QALYs. Sensitivity analyses showed that continuous support in the first birth was cost-effective even when varying the estimate of lost wages of the support person up to $708. CONCLUSION: Continuous labor support from a layperson leads to fewer cesarean births, improved outcomes, decreased costs, and increased QALYs. This highlights the need to increase women's access to continuous layperson support during labor and birth uninhibited by financial and institutional barriers.

The Cost-Effectiveness of Professional Doula Care for a Woman's First Two Births: A Decision Analysis Model.

INTRODUCTION: Multiple studies have demonstrated the benefits of intrapartum doula care, including lower risk for cesarean birth and shortened labor time for nulliparous women. However, analyses investigating the cost-effectiveness of doula care are limited. This study evaluated the potential cost-effectiveness of professional doula support during a woman's first birth in a theoretical population of US women, with all women having a second birth without doula care. METHODS: A cost-effectiveness model was designed to compare outcomes in women with a professional doula versus no doula labor support. A theoretical cohort of 1.6 million women, the approximate number of annual low-risk, nulliparous, term, singleton births in the United States, was used. Outcomes included mode of birth, maternal death, uterine rupture, cesarean hysterectomy, costs, and quality-adjusted life years (QALYs). Probability estimates used in the model were derived from the literature, and a cost-effectiveness threshold was set at $100,000 per QALY. Sensitivity analyses were used to investigate the robustness of the results. RESULTS: In this theoretical model, professional doula care during the first birth resulted in fewer cesarean births and improved QALYs. Additionally, doula support resulted in 202,538 fewer cesarean births, 46 fewer maternal deaths secondary to fewer cesarean births, 99 fewer uterine ruptures, and 26 fewer hysterectomies, with an additional cost of $185 million and 7617 increased QALYs for the first and subsequent births. Sensitivity analyses demonstrated a professional doula was potentially cost-saving up to $884 and cost-effective up to $1360 per doula. DISCUSSION: Professional doula care during a woman's first birth may lead to improved outcomes and increased QALYs during her first and second births. Given the limitations of this analysis, the cost-effectiveness estimate is likely conservative, further supporting broader integration of professional doulas into the US maternity care system and highlighting the need for higher doula care reimbursement.

Monoclonal Antibodies Reveal Dynamic Plasticity Between Lgr5- and Bmi1-Expressing Intestinal Cell Populations.

BACKGROUND & AIMS: Continual renewal of the intestinal epithelium is dependent on active- and slow-cycling stem cells that are confined to the crypt base. Tight regulation of these stem cell populations maintains homeostasis by balancing proliferation and differentiation to support critical intestinal functions. The hierarchical relation of discrete stem cell populations in homeostasis or during regenerative epithelial repair remains controversial. Although recent studies have supported a model for the active-cycling leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5)+ intestinal stem cell (ISC) functioning upstream of the slow-cycling B lymphoma Mo-MLV insertion region 1 homolog (Bmi1)-expressing cell, other studies have reported the opposite relation. Tools that facilitate simultaneous analyses of these populations are required to evaluate their coordinated function. METHODS: We used novel monoclonal antibodies (mAbs) raised against murine intestinal epithelial cells in conjunction with ISC-green fluorescent protein (GFP) reporter mice to analyze relations between ISC populations by microscopy. Ex vivo 3-dimensional cultures, flow cytometry, and quantitative reverse-transcription polymerase chain reaction analyses were performed. RESULTS: Two novel mAbs recognized distinct subpopulations of the intestinal epithelium and when used in combination permitted isolation of discrete Lgr5GFP and Bmi1GFP-enriched populations with stem activity. Growth from singly isolated Lgr5GFP ISCs gave rise to small spheroids. Spheroids did not express Lgr5GFP and instead up-regulated Bmi1GFP expression. Conversely, Bmi1-derived spheroids initiated Lgr5GFP expression as crypt domains were established. CONCLUSIONS: These data showed the functional utility of murine mAbs in the isolation and investigation of Lgr5GFP and Bmi1GFP ISC-enriched populations. Ex vivo analyses showed hierarchical plasticity between different ISC-expressing states; specifically Lgr5GFP ISCs gave rise to Bmi1GFP cells, and vice versa. These data highlight the impact of temporal and physiological context on unappreciated interactions between Lgr5GFP and Bmi1GFP cells during crypt formation.

Cell Adhesion Molecule CD166/ALCAM Functions Within the Crypt to Orchestrate Murine Intestinal Stem Cell Homeostasis.

BACKGROUND & AIMS: Intestinal epithelial homeostasis is maintained by active-cycling and slow-cycling stem cells confined within an instructive crypt-based niche. Exquisite regulating of these stem cell populations along the proliferation-to-differentiation axis maintains a homeostatic balance to prevent hyperproliferation and cancer. Although recent studies focus on how secreted ligands from mesenchymal and epithelial populations regulate intestinal stem cells (ISCs), it remains unclear what role cell adhesion plays in shaping the regulatory niche. Previously we have shown that the cell adhesion molecule and cancer stem cell marker, CD166/ALCAM (activated leukocyte cell adhesion molecule), is highly expressed by both active-cycling Lgr5+ ISCs and adjacent Paneth cells within the crypt base, supporting the hypothesis that CD166 functions to mediate ISC maintenance and signal coordination. METHODS: Here we tested this hypothesis by analyzing a CD166-/- mouse combined with immunohistochemical, flow cytometry, gene expression, and enteroid culture. RESULTS: We found that animals lacking CD166 expression harbored fewer active-cycling Lgr5+ ISCs. Homeostasis was maintained by expansion of the transit-amplifying compartment and not by slow-cycling Bmi1+ ISC stimulation. Loss of active-cycling ISCs was coupled with deregulated Paneth cell homeostasis, manifested as increased numbers of immature Paneth progenitors due to decreased terminal differentiation, linked to defective Wnt signaling. CD166-/- Paneth cells expressed reduced Wnt3 ligand expression and depleted nuclear ß-catenin. CONCLUSIONS: These data support a function for CD166 as an important cell adhesion molecule that shapes the signaling microenvironment by mediating ISC-niche cell interactions. Furthermore, loss of CD166 expression results in decreased ISC and Paneth cell homeostasis and an altered Wnt microenvironment.

Defining a stem cell hierarchy in the intestine: markers, caveats and controversies.

The past decade has appreciated rapid advance in identifying the once elusive intestinal stem cell (ISC) populations that fuel the continual renewal of the epithelial layer. This advance was largely driven by identification of novel stem cell marker genes, revealing the existence of quiescent, slowly- and active-cycling ISC populations. However, a critical barrier for translating this knowledge to human health and disease remains elucidating the functional interplay between diverse stem cell populations. Currently, the precise hierarchical and regulatory relationships between these ISC populations are under intense scrutiny. The classical theory of a linear hierarchy, where quiescent and slowly-cycling stem cells self-renew but replenish an active-cycling population, is well established in other rapidly renewing tissues such as the haematopoietic system. Efforts to definitively establish a similar stem cell hierarchy within the intestinal epithelium have yielded conflicting results, been difficult to interpret, and suggest non-conventional alternatives to a linear hierarchy. While these new and potentially paradigm-shifting discoveries are intriguing, the field will require development of a number of critical tools, including highly specific stem cell marker genes along with more rigorous experimental methodologies, to delineate the complex cellular relationships within this dynamic organ system.

Mechanisms of resistance of Porphyromonas gingivalis to killing by serum complement.

The complement system plays an important role in the host defense against infection, and the formation of the terminal complement complex on the bacterial surface has been shown to be particularly important in killing of gram-negative bacteria. The gram-negative periodontal pathogen Porphyromonas gingivalis is resistant to complement killing, and possible mechanisms suggested for this resistance include protease production and capsule formation. In this study, P. gingivalis Arg- and Lys-gingipain deletion mutants and polysaccharide synthesis deletion mutants have been used to investigate these hypotheses. When Arg- and Lys-gingipain protease mutants were incubated in 20% normal human serum, deposition of complement components on the cell surface was significantly increased compared to that for the wild-type organism. However, despite the increased deposition, the protease mutants maintained resistance to killing and their viability was equal to that seen with heat-inactivated serum. Similar data were obtained when the wild-type organism was treated with gingipain protease inhibitors. K-antigen expression mutants were also resistant to killing. However, mutants which no longer synthesized a surface anionic polysaccharide (APS) (a phosphorylated branched mannan) were extremely sensitive to serum killing. These mutants lack the organized dense glycan surface layer present on the parent strain on the basis of electron microscopy. We conclude that the production of APS at the surface of P. gingivalis rather than Arg- and Lys-gingipain synthesis is the principal mechanism of serum resistance in P. gingivalis.

Identification and characterization of the capsular polysaccharide (K-antigen) locus of Porphyromonas gingivalis.

Capsular polysaccharides of gram-negative bacteria play an important role in maintaining the structural integrity of the cell in hostile environments and, because of their diversity within a given species, can act as useful taxonomic aids. In order to characterize the genetic locus for capsule biosynthesis in the oral gram-negative bacterium Porphyromonas gingivalis, we analyzed the genome of P. gingivalis W83 which revealed two candidate loci at PG0106-PG0120 and PG1135-PG1142 with sufficient coding capacity and appropriate gene functions based on comparisons with capsule-coding loci in other bacteria. Insertion and deletion mutants were prepared at PG0106-PG0120 in P. gingivalis W50-a K1 serotype. Deletion of PG0109-PG0118 and PG0116-PG0120 both yielded mutants which no longer reacted with antisera to K1 serotypes. Restriction fragment length polymorphism analysis of the locus in strains representing all six K-antigen serotypes and K(-) strains demonstrated significant variation between serotypes and limited conservation within serotypes. In contrast, PG1135-PG1142 was highly conserved in this collection of strains. Sequence analysis of the capsule locus in strain 381 (K(-) strain) demonstrated synteny with the W83 locus but also significant differences including replacement of PG0109-PG0110 with three unique open reading frames, deletion of PG0112-PG0114, and an internal termination codon within PG0106, each of which could contribute to the absence of capsule expression in this strain. Analysis of the Arg-gingipains in the capsule mutants of strain W50 revealed no significant changes to the glycan modifications of these enzymes, which indicates that the glycosylation apparatus in P. gingivalis is independent of the capsule biosynthetic machinery.

Using early troponin I testing to improve cardiac care.

Quicker test results following suspected myocardial infarction reduce the time required to make decisions on treatment, allowing it to begin earlier and facilitating a well-planned discharge. This article describes how the introduction of early diagnostic testing allowed the timely treatment of patients admitted to a medical admissions unit with chest pain.

Multidisciplinary meetings in medical admissions units.

Multidisciplinary working was introduced in a medical admissions unit to improve the discharge process. The number of patients discharged increased as did the opportunities for discharge because they took place throughout the week including weekends. The number of medical patients occupying surgical beds decreased by 100 per cent, which reduced disruption to elective surgery schedules.

Glycosylation of the Arg-gingipains of Porphyromonas gingivalis and comparison with glycoconjugate structure and synthesis in other bacteria.

Post-translational modification of proteins by covalent attachment of sugars to the protein backbone (protein glycosylation) is the most common post-translational modification in the eucaryotic cell. However, the addition of carbohydrates to proteins of Eubacteria and Archaea has been demonstrated and accepted only recently. There is now a rapidly expanding list of bacterial glycoproteins that have been characterised from a variety of different organisms including many important pathogens. The Arg-gingipains of Porphyromonas gingivalis are recent additions to this list. In this review we present a summary of our investigations on the structure of the glycan additions to these proteolytic enzymes, the genetics of the glycosylation process and some of the effects on enzyme function and recognition. These findings are placed in the context of the current status of understanding of glycoconjugate structure and synthesis in other bacteria. Given the importance of glycosylation of eucaryotic proteins to their stability, structure, resistance to proteolysis and recognition, the modifications to the proteases described in the present report are likely to have a functional role in the properties of these enzymes in periodontal disease.