In critically ill patients, anti-anaerobic antibiotics increase risk of adverse clinical outcomes.

BACKGROUND: Critically ill patients routinely receive antibiotics with activity against anaerobic gut bacteria. However, in other disease states and animal models, gut anaerobes are protective against pneumonia, organ failure and mortality. We therefore designed a translational series of analyses and experiments to determine the effects of anti-anaerobic antibiotics on the risk of adverse clinical outcomes among critically ill patients. METHODS: We conducted a retrospective single-centre cohort study of 3032 critically ill patients, comparing patients who did and did not receive early anti-anaerobic antibiotics. We compared intensive care unit outcomes (ventilator-associated pneumonia (VAP)-free survival, infection-free survival and overall survival) in all patients and changes in gut microbiota in a subcohort of 116 patients. In murine models, we studied the effects of anaerobe depletion in infectious (Klebsiella pneumoniae and Staphylococcus aureus pneumonia) and noninfectious (hyperoxia) injury models. RESULTS: Early administration of anti-anaerobic antibiotics was associated with decreased VAP-free survival (hazard ratio (HR) 1.24, 95% CI 1.06-1.45), infection-free survival (HR 1.22, 95% CI 1.09-1.38) and overall survival (HR 1.14, 95% CI 1.02-1.28). Patients who received anti-anaerobic antibiotics had decreased initial gut bacterial density (p=0.00038), increased microbiome expansion during hospitalisation (p=0.011) and domination by Enterobacteriaceae spp. (p=0.045). Enterobacteriaceae were also enriched among respiratory pathogens in anti-anaerobic-treated patients (p<2.2×10-16). In murine models, treatment with anti-anaerobic antibiotics increased susceptibility to Enterobacteriaceae pneumonia (p<0.05) and increased the lethality of hyperoxia (p=0.0002). CONCLUSIONS: In critically ill patients, early treatment with anti-anaerobic antibiotics is associated with increased mortality. Mechanisms may include enrichment of the gut with respiratory pathogens, but increased mortality is incompletely explained by infections alone. Given consistent clinical and experimental evidence of harm, the widespread use of anti-anaerobic antibiotics should be reconsidered.

Overall survival indirect treatment comparison between brigatinib and alectinib for the treatment of front-line anaplastic lymphoma kinase-positive non-small cell lung cancer using data from ALEX and final results from ALTA-1L.

BACKGROUND: Second-generation anaplastic lymphoma kinase (ALK) gene targeted tyrosine kinase inhibitors (TKIs) alectinib and brigatinib have shown efficacy as front-line treatments for ALK-positive non-small cell lung cancer (NSCLC). No head-to-head data are currently available for brigatinib vs alectinib in the ALK-TKI-naive population. OBJECTIVE: To estimate the relative overall survival (OS) for brigatinib vs alectinib with indirect treatment comparisons (ITCs) using ALEX and ALTA-1L clinical trial data. METHODS: The latest aggregate data from the ALEX trial and final patient-level data from ALTA-1L were used. ITCs were conducted with/without treatment crossover adjustments to estimate relative OS. Bucher methods, anchored matching-adjusted indirect comparisons (MAICs) and unanchored MAICs were employed in ITCs without treatment crossover adjustments. An inverse probability of censoring weight Cox model, a marginal structure model and rank-preserving structural failure time models (with/without re-censoring) within an anchored MAIC were used in ITCs with treatment crossover adjustments. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. RESULTS: HRs for brigatinib vs alectinib for relative OS generated from ITCs without treatment crossover adjustments ranged from 0.90 (95% CI: 0.59-1.38) in the unanchored MAIC to 1.20 (95% CI: 0.69-2.11) using the Bucher method. Methods employing treatment switching adjustments estimated HRs for relative OS ranging from 0.74 (95% CI: 0.38-1.45) to 1.11 (95% CI: 0.63-1.94). Results from all ITCs did not indicate statistically different survival profiles. CONCLUSION: Regardless of ITC methodology, OS is comparable for brigatinib vs alectinib in patients with ALK+ NSCLC previously untreated with an ALK inhibitor.

Indirect comparisons of brigatinib and alectinib for front-line ALK-positive non-small-cell lung cancer.

Aim: To conduct an indirect treatment comparison (ITC) of the relative efficacy of brigatinib and alectinib for progression-free survival in people with tyrosine kinase inhibitor (TKI)-naive ALK-positive non-small-cell lung cancer (NSCLC). Methods: Final aggregate and patient-level data from the ALTA-1L trial comparing brigatinib to crizotinib and published aggregate data from ALEX (comparing alectinib to crizotinib) were contrasted using Bucher ITC and matching-adjusted indirect comparisons (MAICs). Results: No statistically significant differences were identified between brigatinib and alectinib in reducing the risk of disease progression overall and in patients with baseline central nervous system metastases. Conclusion: Brigatinib appeared similar to alectinib in reducing risk of disease progression for people with TKI-naive ALK-positive NSCLC.

Patients with advanced non-small-cell lung cancer (NSCLC) who have a genetic marker called rearrangement in the anaplastic lymphoma kinase, or ALK-positive disease, are treated with targeted medications taken by mouth. Two medications, alectinib and brigatinib, are both considered first-line treatment for these patients but have not been compared head-to-head. Recently, updated clinical trial results were published for these medications. The present study utilized these updated results and advanced statistical tests to indirectly compare the effectiveness of the two treatments to help guide clinical treatment choices. Results showed brigatinib and alectinib have a similar magnitude of effect in decreasing the risk of a patient with ALK-positive NSCLC developing worsening disease.

Effects of Transportation of IV Bags Containing Protein Formulations Via Hospital Pneumatic Tube System: Particle Characterization by Multiple Methods.

In hospitals, often drug products in intravenous (IV) bags are transported via pneumatic tube systems (PTS). The goal of this study was to evaluate the effects of such transportation of protein products on particle formation in polyvinyl chloride (PVC) and polyolefin (PO) IV bags, containing either IV saline or dextrose. We studied intravenous immunoglobulin (IVIG) and a monoclonal antibody (mAb). Particles were quantified with flow imaging, light obscuration and nanoparticle tracking analysis. PTS transportation of IVIG caused large increases in protein particle concentrations, with much greater increases observed in saline than in dextrose. The increases were greater in IV solutions in PO than those in PVC bags. With the mAb, PTS transportation in saline caused increases in protein particle levels in PO bags, but not in PVC bags. Transportation in dextrose did not result in significant increases in mAb particle concentrations in IV bags made of either material. Overall, the results document that the PTS transportation can result in large increases in protein particles and that magnitude of these increases depends the protein itself, the bag material and the IV solution. The main conclusion is that protein products in IV solutions should not be transported in hospital PTS.

The International Patient Summary and the Summarization Requirement.

The 'patient summary' has an important role in delivering continuity and coordination of a person's health and care. 'patient summary' implementations are pervasive and important to both healthcare providers and to their subjects of care. The digital version of the patient summary, however, often falls short of its intended functionality and its potential value. The requirements of summarization and what they mean for the communication situation in which the summarization of health and care data takes place has been analyzed. The purpose is to understand the limitations and potential of current digital solutions for communicating a 'patient summary'. The International Patient Summary (IPS) standard is a step towards communicating safe, relevant patient summaries for use throughout the world. To meet this grand challenge, the IPS can capitalize upon the inherent capacity and competence of all people to produce and consume summaries.

Tracheostomy for COVID-19 respiratory failure: timing, ventilatory characteristics, and outcomes.

BACKGROUND: Whereas data from the pre-pandemic era have demonstrated that tracheostomy can accelerate liberation from the ventilator, reduce need for sedation, and facilitate rehabilitation, concerns for healthcare worker safety have led to disagreement on tracheostomy placement in COVID-19 patients. Data on COVID-19 patients undergoing tracheostomy may inform best practices. Thus, we report a retrospective institutional cohort experience with tracheostomy in ventilated patients with COVID-19, examining associations between time to tracheostomy and duration of mechanical ventilation in relation to patient characteristics, clinical course, and survival. METHODS: Clinical data were extracted for all COVID-19 tracheostomies performed at a quaternary referral center from April-July 2020. Outcomes studied included mortality, adverse events, duration of mechanical ventilation, and time to decannulation. RESULTS: Among 64 COVID-19 tracheostomies (13% of COVID-19 hospitalizations), patients were 64% male and 42% African American, with a median age of 54 (range, 20-89). Median time to tracheostomy was 22 (range, 7-60) days and median duration of mechanical ventilation was 39.4 (range, 20-113) days. Earlier tracheostomy was associated with shortened mechanical ventilation (R2=0.4, P<0.01). Median decannulation time was 35.3 (range, 7-79) days. There was 19% mortality and adverse events in 45%, mostly from bleeding in therapeutically anticoagulated patients. CONCLUSIONS: Tracheostomy was associated with swifter liberation from the ventilator and acceptable safety for physicians in this series of critically ill COVID-19 patients. Patient mortality was not increased relative to historical data on acute respiratory distress syndrome (ARDS). Future studies are required to establish conclusions of causality regarding tracheostomy timing with mechanical ventilation, complications, or mortality in COVID-19 patients.

Comparing Clinical Features and Outcomes in Mechanically Ventilated Patients with COVID-19 and Acute Respiratory Distress Syndrome.

Rationale: Patients with severe coronavirus disease (COVID-19) meet clinical criteria for the acute respiratory distress syndrome (ARDS), yet early reports suggested they differ physiologically and clinically from patients with non-COVID-19 ARDS, prompting treatment recommendations that deviate from standard evidence-based practices for ARDS. Objectives: To compare respiratory physiology, clinical outcomes, and extrapulmonary clinical features of severe COVID-19 with non-COVID-19 ARDS. Methods: We performed a retrospective cohort study, comparing 130 consecutive mechanically ventilated patients with severe COVID-19 with 382 consecutive mechanically ventilated patients with non-COVID-19 ARDS. Initial respiratory physiology and 28-day outcomes were compared. Extrapulmonary manifestations (inflammation, extrapulmonary organ injury, and coagulation) were compared in an exploratory analysis. Results: Comparison of patients with COVID-19 and non-COVID-19 ARDS suggested small differences in respiratory compliance, ventilatory efficiency, and oxygenation. The 28-day mortality was 30% in patients with COVID-19 and 38% in patients with non-COVID-19 ARDS. In adjusted analysis, point estimates of differences in time to breathing unassisted at 28 days (adjusted subdistributional hazards ratio, 0.98 [95% confidence interval (CI), 0.77-1.26]) and 28-day mortality (risk ratio, 1.01 [95% CI, 0.72-1.42]) were small for COVID-19 versus non-COVID-19 ARDS, although the confidence intervals for these estimates include moderate differences. Patients with COVID-19 had lower neutrophil counts but did not differ in lymphocyte count or other measures of systemic inflammation. Conclusions: In this single-center cohort, we found no evidence for large differences between COVID-19 and non-COVID-19 ARDS. Many key clinical features of severe COVID-19 were similar to those of non-COVID-19 ARDS, including respiratory physiology and clinical outcomes, although our sample size precludes definitive conclusions. Further studies are needed to define COVID-19-specific pathophysiology before a deviation from evidence-based treatment practices can be recommended.

The International Patient Summary Standard and the Extensibility Requirement.

The International Patient Summary Standard (EN 17269) normalizes the dataset within the European Guideline on cross-border exchange of a patient summary. This dataset has been widely appreciated and been taken as the basis for projects in both Europe and wider afield, e.g. U.S.A, Canada and more. The dataset is a relatively mature dataset and it is currently in its third iteration (i.e., 2013, 2016, 2020). Even so, to move from a policy-driven guideline to a formal standard was not straight forward. The paper describes how the 'minimal and non-exhaustive' dataset could be the basis for a reference standard; one that was intended to facilitate both an 'implementable' and 'sustainable' solution. In particular, the requirement of 'extensibility' for the standard dataset had to be addressed.

Identifying Principles for the Construction of an Ontology-Based Knowledge Base: A Case Study Approach.

BACKGROUND: Ontologies are key enabling technologies for the Semantic Web. The Web Ontology Language (OWL) is a semantic markup language for publishing and sharing ontologies. OBJECTIVE: The supply of customizable, computable, and formally represented molecular genetics information and health information, via electronic health record (EHR) interfaces, can play a critical role in achieving precision medicine. In this study, we used cystic fibrosis as an example to build an Ontology-based Knowledge Base prototype on Cystic Fibrobis (OntoKBCF) to supply such information via an EHR prototype. In addition, we elaborate on the construction and representation principles, approaches, applications, and representation challenges that we faced in the construction of OntoKBCF. The principles and approaches can be referenced and applied in constructing other ontology-based domain knowledge bases. METHODS: First, we defined the scope of OntoKBCF according to possible clinical information needs about cystic fibrosis on both a molecular level and a clinical phenotype level. We then selected the knowledge sources to be represented in OntoKBCF. We utilized top-to-bottom content analysis and bottom-up construction to build OntoKBCF. Protégé-OWL was used to construct OntoKBCF. The construction principles included (1) to use existing basic terms as much as possible; (2) to use intersection and combination in representations; (3) to represent as many different types of facts as possible; and (4) to provide 2-5 examples for each type. HermiT 1.3.8.413 within Protégé-5.1.0 was used to check the consistency of OntoKBCF. RESULTS: OntoKBCF was constructed successfully, with the inclusion of 408 classes, 35 properties, and 113 equivalent classes. OntoKBCF includes both atomic concepts (such as amino acid) and complex concepts (such as "adolescent female cystic fibrosis patient") and their descriptions. We demonstrated that OntoKBCF could make customizable molecular and health information available automatically and usable via an EHR prototype. The main challenges include the provision of a more comprehensive account of different patient groups as well as the representation of uncertain knowledge, ambiguous concepts, and negative statements and more complicated and detailed molecular mechanisms or pathway information about cystic fibrosis. CONCLUSIONS: Although cystic fibrosis is just one example, based on the current structure of OntoKBCF, it should be relatively straightforward to extend the prototype to cover different topics. Moreover, the principles underpinning its development could be reused for building alternative human monogenetic diseases knowledge bases.

Comparative Effectiveness of Adding Alogliptin to Metformin Plus Sulfonylurea with Other DPP-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Alogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), approved for the treatment of type 2 diabetes mellitus (T2DM). There currently exists no comparative data to support the use of alogliptin in combination with metformin (met) and sulfonylurea (SU). A decision-focused network meta-analysis (NMA) was performed to compare the relative efficacy and safety of alogliptin 25 mg once daily to other DPP-4 inhibitors as part of a triple therapy regimen for patients inadequately controlled on metformin and SU dual therapy. METHODS: A systematic literature review was conducted to identify published papers of randomized controlled trials (RCTs) that compared alogliptin with other DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) at their Summary of Product Characteristics (SmPC) recommended daily doses, added on to metformin and SU. Comprehensive comparative analysis involving frequentist meta-analysis and Bayesian NMA compared alogliptin to each DPP-4 inhibitor separately and collectively as a group. Quasi-random effect models were introduced when random effect models could not be estimated. RESULTS: The review identified 2186 articles, and 94 full-text articles were assessed for eligibility. Eight RCTs contained appropriate data for inclusion in the NMA. All analyses over all trial population sets produced very similar results, and show that alogliptin 25 mg is as least as effective (as measured by change in HbA1c from baseline, but supported by other outcome measures: change in body weight and FPG from baseline) and safe (as measured by incidence of hypoglycemia and adverse events leading to study discontinuation) as all the other DPP-4 inhibitors in triple therapy. CONCLUSION: This decision-focused systematic review and NMA demonstrated alogliptin 25 mg daily to have similar efficacy and safety compared to other DPP-4 inhibitors, for the treatment of T2DM in adults inadequately controlled on metformin and SU. (Funded by Takeda Development Centre Americas; EXAMINE ClinicalTrials.gov number, NCT00968708).

A 3D assessment and feedback tool for Ankylosing Spondylitis from the perspective of healthcare professionals.

To investigate the utility of 3D visualization technology to augment assessment and feedback for Ankylosing Spondylitis (AS), a visualization prototype was developed, and both subjective and objective measures of current assessment instruments were compared. To verify and establish a base-line for the prototype's effectiveness, motion data and measurement data from a healthy adult in a laboratory environment were collected. To validate the prototype, a qualitative evaluation was undertaken using multiple methods including a pilot study, focus groups, and individual interviews. Research subjects comprised physiotherapists in clinical practice and academia and content analysis of their responses was used to substantiate the findings. The prototype enhanced both assessment and feedback of AS from the physiotherapist's perspective and they believed it to be superior to the current methods used in practice for assessing the condition and in documenting variations for subsequent treatment. The physiotherapists believed that such a system had potential to encourage multidisciplinary working, and to be patient-centric, both with respect to the process of treatment and with regard to the convenience it offered to patients in managing their own condition. 3D visualization of AS symptoms and its treatment via exercise is a valuable technique as demonstrated by the prototype system.

Interoperability standards enabling cross-border patient summary exchange.

In an increasingly mobile world, many citizens and professionals are frequent travellers. Access during unplanned care to their patient summary, their most essential health information in a form physicians in another country can understand can impact not only their safety, but also the quality and effectiveness of care. International health information technology (HIT) standards such as HL7 CDA have been developed to advance interoperability. Implementation guides (IG) and IHE profiles constrain standards and make them fit for the purpose of specific use cases. A joint effort between HL7, IHE, and HealthStory created Consolidated CDA (C-CDA), a set of harmonized CDA IGs for the US that is cited in the Meaning Use II (MU-II) regulation. In the EU, the Patient Summary (PS) Guideline recently adopted, cites the epSOS IG also based on HL7 CDA, to support cross-border care in the EU and inform national eHealth programs. Trillium Bridge project supports international standards development by extending the EU PS Guideline and MU-II in the transatlantic setting. This paper presents preliminary findings from comparing patient summaries in the EU and US and reflects on the challenge of implementing interoperable eHealth systems in the cross-border or transatlantic setting.

Integration of an OWL-DL knowledge base with an EHR prototype and providing customized information.

When clinicians use electronic health record (EHR) systems, their ability to obtain general knowledge is often an important contribution to their ability to make more informed decisions. In this paper we describe a method by which an external, formal representation of clinical and molecular genetic knowledge can be integrated into an EHR such that customized knowledge can be delivered to clinicians in a context-appropriate manner.Web Ontology Language-Description Logic (OWL-DL) is a formal knowledge representation language that is widely used for creating, organizing and managing biomedical knowledge through the use of explicit definitions, consistent structure and a computer-processable format, particularly in biomedical fields. In this paper we describe: 1) integration of an OWL-DL knowledge base with a standards-based EHR prototype, 2) presentation of customized information from the knowledge base via the EHR interface, and 3) lessons learned via the process. The integration was achieved through a combination of manual and automatic methods. Our method has advantages for scaling up to and maintaining knowledge bases of any size, with the goal of assisting clinicians and other EHR users in making better informed health care decisions.

Mapping the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) to EQ-5D utility scores.

PURPOSE: To develop a mapping algorithm for the estimation of EQ-5D-based utility scores from observed 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) scores, a disease-specific, patient-reported outcome measure used in several retinal disorders to evaluate vision-specific functioning. METHODS: The dataset comprised 951 paired EQ-5D/NEI VFQ-25 observations from 344 patients in RESTORE, a 12-month, randomized, double-blind trial in individuals with visual impairment due to diabetic macular edema. EQ-5D index scores (utilities) were calculated based on the UK tariff. We evaluated 11 models using predictor sets based on the NEI VFQ-25 subscales to estimate utility as a function of NEI VFQ-25 score, based on four modeling techniques. Model performance was assessed by 10-fold cross-validation comparing root mean squared error (RMSE), mean absolute error (MAE) and correlation with EQ-5D score (Pearson and Spearman correlation coefficients). RESULTS: Mapping results were similar across all techniques and predictor sets. The reverse two-part generalized estimating equation model used fewest predictors and had the best predictive performance (RMSE 0.200, MAE 0.140). Predicted and original EQ-5D values were not strongly correlated (squared Spearman correlation coefficient, 0.34). CONCLUSIONS: Although mapping disease-specific instruments to EQ-5D utilities is a preferred method by some reimbursement bodies, finding an appropriate mapping equation is not straightforward. In this study, mapping NEI VFQ-25 scores to EQ-5D utilities provided low predictive power, independent of the modeling methodology applied, suggesting an inability of the EQ-5D to discriminate vision-related activities, and highlighting that mapping exercises may lead to inaccurate utility values that do not represent patients' preferences.

Mapping EQ-5D utility scores from the Incontinence Quality of Life Questionnaire among patients with neurogenic and idiopathic overactive bladder.

OBJECTIVES: To provide a mapping algorithm for estimating EuroQol five-dimensional (EQ-5D) questionnaire index scores from the Incontinence-specific Quality of Life questionnaire (I-QOL) based on nationally representative samples of patients with idiopathic or neurogenic overactive bladder (OAB) using EQ-5D questionnaire preference valuations based on both the UK and US general populations. METHODS: Analyses were conducted for 2505 patients from the Adelphi Overactive Bladder Disease Specific Programme, a cross-sectional study of patients with idiopathic or neurogenic OAB, undertaken in the United States and Europe in 2010. A range of statistical modeling techniques was used. Tenfold cross-validation techniques were used to calculate mean absolute error (MAE) and root mean squared error (RMSE) goodness-of-fit statistics. Various predictor lists, together with a method combining stepwise selection with multivariable fractional polynomial techniques to allow nonlinear relationships to feature, were pursued. RESULTS: Choice of predictors was consistent for both the UK and US EQ-5D questionnaire tariffs. For idiopathic, the best model included the I-QOL total score and age (both modeled nonlinearly.) For neurogenic, the best model was the I-QOL social embarrassment domain score modeled linearly only. Best-fit results were better in the idiopathic (n = 2351; MAE = 0.10; RMSE = 0.14) than in the neurogenic sample (n = 254; MAE = 0.17; RMSE = 0.22). CONCLUSIONS: This research provides algorithms for mapping EQ-5D questionnaire index scores from the I-QOL, allowing calculation of appropriate preference-based health-related quality-of-life scores for use in cost-effectiveness analyses when only I-QOL data are available. The strongest results were for idiopathic patients, but those for neurogenic are consistent with those of other published mapping studies.

Incorporating personalized gene sequence variants, molecular genetics knowledge, and health knowledge into an EHR prototype based on the Continuity of Care Record standard.

OBJECTIVES: The current volume and complexity of genetic tests, and the molecular genetics knowledge and health knowledge related to interpretation of the results of those tests, are rapidly outstripping the ability of individual clinicians to recall, understand and convey to their patients information relevant to their care. The tailoring of molecular genetics knowledge and health knowledge in clinical settings is important both for the provision of personalized medicine and to reduce clinician information overload. In this paper we describe the incorporation, customization and demonstration of molecular genetic data (mainly sequence variants), molecular genetics knowledge and health knowledge into a standards-based electronic health record (EHR) prototype developed specifically for this study. METHODS: We extended the CCR (Continuity of Care Record), an existing EHR standard for representing clinical data, to include molecular genetic data. An EHR prototype was built based on the extended CCR and designed to display relevant molecular genetics knowledge and health knowledge from an existing knowledge base for cystic fibrosis (OntoKBCF). We reconstructed test records from published case reports and represented them in the CCR schema. We then used the EHR to dynamically filter molecular genetics knowledge and health knowledge from OntoKBCF using molecular genetic data and clinical data from the test cases. RESULTS: The molecular genetic data were successfully incorporated in the CCR by creating a category of laboratory results called "Molecular Genetics" and specifying a particular class of test ("Gene Mutation Test") in this category. Unlike other laboratory tests reported in the CCR, results of tests in this class required additional attributes ("Molecular Structure" and "Molecular Position") to support interpretation by clinicians. These results, along with clinical data (age, sex, ethnicity, diagnostic procedures, and therapies) were used by the EHR to filter and present molecular genetics knowledge and health knowledge from OntoKBCF. CONCLUSIONS: This research shows a feasible model for delivering patient sequence variants and presenting tailored molecular genetics knowledge and health knowledge via a standards-based EHR system prototype. EHR standards can be extended to include the necessary patient data (as we have demonstrated in the case of the CCR), while knowledge can be obtained from external knowledge bases that are created and maintained independently from the EHR. This approach can form the basis for a personalized medicine framework, a more comprehensive standards-based EHR system and a potential platform for advancing translational research by both disseminating results and providing opportunities for new insights into phenotype-genotype relationships.

Next generation of individual account pension reforms in Latin America.

Latin America led the world in introducing individual retirement accounts intended to complement or replace defined benefit state-sponsored, pay-as-you-go systems. After Chile implemented the first system in 1981, a number of other Latin American countries incorporated privately managed individual accounts as part of their retirement income systems beginning in the 1990s. This article examines the subsequent "reform of the reform" of these pension systems, with a focus on the recent overhaul of the Chilean system and major reforms in Mexico, Peru, and Colombia. The authors analyze key elements of pension reform in the region relating to individual accounts: system coverage, fees, competition, investment, the impact of gender on benefits, financial education, voluntary savings, and payouts.

The use of osteo-conductive stem-cells allograft in lumbar interbody fusion procedures: an alternative to recombinant human bone morphogenetic protein.

UNLABELLED: The use of autogenous bone graft in spinal fusion is progressively declining. Different allografts including the human bone morphogenetic protein have been proposed to facilitate fusion rates but are associated with various adverse effects. Osteocel belongs to a new class of allograft tissue material that is a re-absorbable biomaterial with allogenic mesenchymal stem cells. The purpose of the present retrospective study was to analyze the clinical effectiveness of mesenchymal stem cells allograft (Osteocel") to achieve radiological arthrodesis in adult patients undergoing lumbar interbody fusion surgery for different indications. Fifty-two consecutive patients received lumbar interbody fusion at one (69%) or two contiguous (31%) levels of lumbar spine for various indications. The mean age was 50 (range, 27 to 77) years; 60% were females; 43% were habitual smokers and 21% had previously failed surgery at the index level(s). OUTCOME MEASURES: Radiographic analyses of fusion by plain films and CT scans. Procedures performed were circumferential fusion (67%), ALIF (17%) and TLIF (16%). Followup radiographic data was analyzed to establish arthrodesis versus failure (pseudarthrosis), number of months until achievement of fusion, and possible factors affecting the fusion rate. Followup ranged from 8 to 27 (median, 14) months. Solid arthrodesis was achieved in 92.3% of patients at median followup time of 5 months (95% Cl; range, 3 to 11 months). Kaplan-Meier survival curves and Mantle-Cox test were conducted to assess the effect of various factors on the rate of fusion. Statistics showed that increasing age (older than 50 years) (p = 0.017) and habitual smoking (p = 0.015) delayed the fusion time and increased the risk of pseudarthrosis. The use of Osteocel allograft is safe and effective in adult patients undergoing lumbar interbody spinal fusion procedure. Increased age and habitual smoking delays fusion but gender, previous surgery at the index level, type of procedure and number of levels do not affect the fusion rates.