Microbial glycan microarrays (MGMs) populated with purified microbial glycans have been used to define the specificity of host immune factors toward microbes in a high throughput manner. However, a ...limitation of such arrays is that glycan presentation may not fully recapitulate the natural presentation that exists on microbes. This raises the possibility that interactions observed on the array, while often helpful in predicting actual interactions with intact microbes, may not always accurately ascertain the overall affinity of a host immune factor for a given microbe. Using galectin-8 (Gal-8) as a probe, we compared the specificity and overall affinity observed using a MGM populated with glycans harvested from various strains of Streptococcus pneumoniae to an intact microbe microarray (MMA). Our results demonstrate that while similarities in binding specificity between the MGM and MMA are apparent, Gal-8 binding toward the MMA more accurately predicted interactions with strains of S. pneumoniae, including the overall specificity of Gal-8 antimicrobial activity. Taken together, these results not only demonstrate that Gal-8 possesses antimicrobial activity against distinct strains of S. pneumoniae that utilize molecular mimicry, but that microarray platforms populated with intact microbes present an advantageous strategy when exploring host interactions with microbes.
Among responders to microbial invasion, neutrophils represent one of the earliest and perhaps most important factors that contribute to initial host defense. Effective neutrophil immunity requires ...their rapid mobilization to the site of infection, which requires efficient extravasation, activation, chemotaxis, phagocytosis, and eventual killing of potential microbial pathogens. Following pathogen elimination, neutrophils must be eliminated to prevent additional host injury and subsequent exacerbation of the inflammatory response. Galectins, expressed in nearly every tissue and regulated by unique sensitivity to oxidative and proteolytic inactivation, appear to influence nearly every aspect of neutrophil function. In this review, we will examine the impact of galectins on neutrophils, with a particular focus on the unique biochemical traits that allow galectin family members to spatially and temporally regulate neutrophil function.
Sepsis is common and expensive, and evidence suggests that sepsis order sets may help to improve care. Very incomplete evidence exists regarding the effects of sepsis order sets on the value of care ...produced by hospitals or the societal costs of sepsis care.
In patients hospitalized for sepsis, is the receipt a of a sepsis order set vs no order set associated with improved value of care, defined as decreased hospital mortality, decreased hospital direct variable costs, and decreased societal spending on hospitalizations?
This retrospective cohort study included patients discharged with sepsis International Classification of Diseases, Tenth Revision, codes over 2 years from a large integrated delivery system. Using a propensity score, sepsis order set users were matched to nonusers to study the association between sepsis order set use and the value of care from the hospital and societal perspective. The association between order set receipt and hospital mortality, direct variable cost, and hospital revenue also were examined in a priori defined subgroups of sepsis severity and hospital mortality.
The study included 97,249 patients, with 52,793 patients (54%) receiving the sepsis order set. The propensity score match analysis included 55,542 patients, with 27,771 patients in each group. Recipients of the sepsis order set showed a 3.3% lower hospital mortality rate and a $1,487 lower median direct variable total cost (P < .01 for both). Median payer-neutral reimbursement (PNR), a proxy for hospital revenue and thus societal costs, was $465 lower for sepsis order set users (P < .01). Receipt of the sepsis order set was associated with a $1,022 increase in contribution margin, the difference between direct variable costs and PNR per patient.
Receipt of the sepsis order set was associated with improved value of care, from both a hospital and societal perspective.
Value-based health care aims to optimize the balance of patient outcomes and health care costs. To improve value in perinatal care using this strategy, standard outcomes must first be defined. The ...objective of this work was to define a minimum, internationally appropriate set of outcome measures for evaluating and improving perinatal care with a focus on outcomes that matter to women and their families.
An interdisciplinary and international Working Group was assembled. Existing literature and current measurement initiatives were reviewed. Serial guided discussions and validation surveys provided consumer input. A series of nine teleconferences, incorporating a modified Delphi process, were held to reach consensus on the proposed Standard Set.
The Working Group selected 24 outcome measures to evaluate care during pregnancy and up to 6 months postpartum. These include clinical outcomes such as maternal and neonatal mortality and morbidity, stillbirth, preterm birth, birth injury and patient-reported outcome measures (PROMs) that assess health-related quality of life (HRQoL), mental health, mother-infant bonding, confidence and success with breastfeeding, incontinence, and satisfaction with care and birth experience. To support analysis of these outcome measures, pertinent baseline characteristics and risk factor metrics were also defined.
We propose a set of outcome measures for evaluating the care that women and infants receive during pregnancy and the postpartum period. While validation and refinement via pilot implementation projects are needed, we view this as an important initial step towards value-based improvements in care.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Coronary artery disease (CAD) outcomes consistently improve when they are routinely measured and provided back to physicians and hospitals. However, few centers around the world ...systematically track outcomes, and no global standards exist. Furthermore, patient‐centered outcomes and longitudinal outcomes are under‐represented in current assessments.
Methods and Results
The nonprofit International Consortium for Health Outcomes Measurement (ICHOM) convened an international Working Group to define a consensus standard set of outcome measures and risk factors for tracking, comparing, and improving the outcomes of CAD care. Members were drawn from 4 continents and 6 countries. Using a modified Delphi method, the ICHOM Working Group defined who should be tracked, what should be measured, and when such measurements should be performed. The ICHOM CAD consensus measures were designed to be relevant for all patients diagnosed with CAD, including those with acute myocardial infarction, angina, and asymptomatic CAD. Thirteen specific outcomes were chosen, including acute complications occurring within 30 days of acute myocardial infarction, coronary artery bypass grafting surgery, or percutaneous coronary intervention; and longitudinal outcomes for up to 5 years for patient‐reported health status (Seattle Angina Questionnaire SAQ‐7, elements of Rose Dyspnea Score, and Patient Health Questionnaire PHQ‐2), cardiovascular hospital admissions, cardiovascular procedures, renal failure, and mortality. Baseline demographic, cardiovascular disease, and comorbidity information is included to improve the interpretability of comparisons.
Conclusions
ICHOM recommends that this set of outcomes and other patient information be measured for all patients with CAD.
Regulatory pathways for protein glycosylation are poorly understood, but expression of branchpoint enzymes is critical. A key branchpoint enzyme is the T-synthase, which directs synthesis of the ...common core 1 O-glycan structure (T-antigen), the precursor structure for most mucin-type O-glycans in a wide variety of glycoproteins. Formation of active T-synthase, which resides in the Golgi apparatus, requires a unique molecular chaperone, Cosmc, encoded on Xq24. Cosmc is the only molecular chaperone known to be lost through somatic acquired mutations in cells. We show that Cosmc is an endoplasmic reticulum (ER)-localized adenosine triphosphate binding chaperone that binds directly to human T-synthase. Cosmc prevents the aggregation and ubiquitin-mediated degradation of the T-synthase. These results demonstrate that Cosmc is a molecular chaperone in the ER required for this branchpoint glycosyltransferase function and show that expression of the disease-related Tn antigen can result from deregulation or loss of Cosmc function.
Purpose National initiatives, such as the UK Improving Access to Psychological Therapies program (IAPT), demonstrate the feasibility of conducting empirical mental health assessments on a large ...scale, and similar initiatives exist in other countries. However, there is a lack of international consensus on which outcome domains are most salient to monitor treatment progress and how they should be measured. The aim of this project was to propose (1) an essential set of outcome domains relevant across countries and cultures, (2) a set of easily accessible patientreported instruments, and (3) a psychometric approach to make scores from different instruments comparable. Methods Twenty-four experts, including ten health outcomes researchers, ten clinical experts from all continents, two patient advocates, and two ICHOM coordinators worked for seven months in a consensus building exercise to develop recommendations based on existing evidence using a structured consensus-driven modified Delphi technique. Results The group proposes to combine an assessment of potential outcome predictors at baseline (47 items: demographics, functional, clinical status, etc.), with repeated assessments of disease-specific symptoms during the treatment process (19 items: symptoms, side effects, etc.), and a comprehensive annual assessment of broader treatment outcomes (45 items: remission, absenteeism, etc.). Further, it is suggested reporting disease-specific symptoms for depression and anxiety on a standardized metric to increase comparability with other legacy instruments. All recommended instruments are provided online (www.ichom.org). Conclusion An international standard of health outcomes assessment has the potential to improve clinical decision making, enhance health care for the benefit of patients, and facilitate scientific knowledge.
IMPORTANCE: Aligning outcome measures for cataract surgery, one of the most frequently performed procedures globally, may facilitate international comparisons that can drive improvements in the ...outcomes most meaningful to patients. OBJECTIVE: To propose a minimum standard set of outcome measures for cataract surgery that enables global comparisons. DESIGN, SETTING, AND PARTICIPANTS: A working group of international experts in cataract outcomes and registries was convened, along with a patient advocate, to agree on a consensus of outcome measures for cataract surgery. In a modified Delphi process, the group met regularly between November 10, 2012, and November 21, 2013, to discuss which outcomes to include in a standard set. Included factors were based on extant literature, existing registries, and the experience of group members. Similarly, a series of consensus discussions were held to determine a set of risk factors to be gathered for each patient. The final shortlist was compiled into a standard set. Analysis was performed from November 22, 2013, to April 5, 2014. MAIN OUTCOMES AND MEASURES: Development of a recommended standard set encompassing preoperative metrics including patient risk factors, intraoperative factors including surgical complications, and postoperative cataract surgery outcomes. RESULTS: The recommended standard set encompasses all patients treated for cataracts by 1 of 4 surgical approaches (phacoemulsification, sutured manual extracapsular cataract extraction, sutureless manual extracapsular cataract extraction, or intracapsular cataract extraction). The recommended metrics to be recorded preoperatively include demographics, ocular history and comorbidities, preoperative visual acuity, and patient-reported visual function. The recommended outcomes were split into intraoperative and postoperative metrics. Intraoperative outcomes include capsule-related problems, dislocation of lens nucleus fragments into the vitreous, and other complications. Postoperative outcomes include visual acuity, refractive error, patient-reported visual function, and early and late complications of surgery. The suggested follow-up for collection of postoperative outcomes is up to 3 months. CONCLUSIONS AND RELEVANCE: A minimum standard set of outcome measures for cataract surgery is important for meaningful comparison across contexts. The proposed data set is a compromise between all useful data and the practicalities of data collection.
Limb-girdle muscular dystrophy type 2B (LGMD2B) is caused by mutations in the dysferlin gene, resulting in non-functional dysferlin, a key protein found in muscle membrane. Treatment options ...available for patients are chiefly palliative in nature and focus on maintaining ambulation. Our hypothesis is that galectin-1 (Gal-1), a soluble carbohydrate binding protein, increases membrane repair capacity and myogenic potential of dysferlin-deficient muscle cells and muscle fibers. To test this hypothesis, we used recombinant human galectin-1 (rHsGal-1) to treat dysferlin-deficient models. We show that rHsGal-1 treatments of 48 h-72 h promotes myogenic maturation as indicated through improvements in size, myotube alignment, myoblast migration, and membrane repair capacity in dysferlin-deficient myotubes and myofibers. Furthermore, increased membrane repair capacity of dysferlin-deficient myotubes, independent of increased myogenic maturation is apparent and co-localizes on the membrane of myotubes after a brief 10min treatment with labeled rHsGal-1. We show the carbohydrate recognition domain of Gal-1 is necessary for observed membrane repair. Improvements in membrane repair after only a 10 min rHsGal-1treatment suggest mechanical stabilization of the membrane due to interaction with glycosylated membrane bound, ECM or yet to be identified ligands through the CDR domain of Gal-1. rHsGal-1 shows calcium-independent membrane repair in dysferlin-deficient and wild-type myotubes and myofibers. Together our novel results reveal Gal-1 mediates disease pathologies through both changes in integral myogenic protein expression and mechanical membrane stabilization.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cellular turnover is associated with exposure of surface phosphatidylserine (PS) in apoptotic cells, leading to their phagocytic recognition and removal. But recent studies indicate that surface PS ...exposure is not always associated with apoptosis. Here we show that several members of the human galectin family of glycan binding proteins (galectins-1, -2, and -4) induce PS exposure in a carbohydrate-dependent fashion in activated, but not resting, human neutrophils and in several leukocyte cell lines. PS exposure is not associated with apoptosis in activated neutrophils. The exposure of PS in cell lines treated with these galectins is sustained and does not affect cell viability. Unexpectedly, these galectins bind well to activated T lymphocytes, but do not induce either PS exposure or apoptosis, indicating that galectin's effects are cell specific. These results suggest novel immunoregulatory contribution of galectins in regulating leukocyte turnover independently of apoptosis.
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