Allen Zhang

Effectiveness of Prevention Strategies for Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis

Iodine contrast medium is an essential component of many diagnostic and therapeutic procedures that involve medical imaging. One important side effect of iodine contrast is contrast-induced nephropathy (CIN), defined as an increase in serum creatinine levels of more than 25% or 44.2 mol/L (0.5 mg/dL) within 3 days of intravascular administration in the absence of an alternative cause (1). Because of increasing use of contrast media in radiologic and cardiologic procedures and the increasing prevalence of persons who are vulnerable to CIN (those with chronic kidney disease, diabetes mellitus, or hypertension, as well as elderly persons), kidney failure due to CIN is a substantial concern (2, 3). The reported incidence varies between 7% and 11% depending on the definition of CIN, study population, and setting (24). Some studies suggest that this incidence may be overestimated (4), especially when intravenous (IV) contrast media are used. An average additional cost of

Comparative evaluation of chitosan, cellulose acetate, and polyethersulfone nanofiber scaffolds for neural differentiation.

10345 is associated with a CIN-related hospital stay (5). Many strategies have been used to prevent CIN. They include oral hydration; volume expansion with sodium chloride or bicarbonate or both; administration of N-acetylcysteine; withdrawal of metformin, angiotensin-converting enzyme inhibitors, angiotensin IIreceptor blockers, or nonsteroidal anti-inflammatory drugs; hemofiltration or hemodialysis; statins; use of low-osmolar contrast media (LOCM), iso-osmolar contrast media (IOCM), or nonionic contrast media; and reducing the volume of contrast media administered. Despite these varied strategies, no clear consensus exists in clinical practice about the most effective intervention to prevent or reduce CIN. Many meta-analyses have been published, but almost all of them have focused on specific therapies or included subspecialtyspecific populations, which reduced the general applicability in clinical practice (611). The route of administration of contrast media may be a confounder because the baseline risk profile of patients having intra-arterial (IA) versus IV procedures may differ. Whether effectiveness of preventive interventions depends on the route of administration or the type of contrast media (IOCM or LOCM, the 2 types now in regular clinical use in the United States) is also unclear. We did a systematic review and meta-analysis to compare the preventive effect of strategies to reduce CIN, including subgroup analyses based on route of administration of contrast media or preventive strategies and the type of contrast media used. Methods We developed a protocol for this systematic review, which we posted online and registered in PROSPERO (CRD42013006217). The complete protocol is in the full report on which this article is based (12). Data Sources and Searches We searched MEDLINE, EMBASE, and the Cochrane Library through 30 June 2015 (Appendix Table). In addition, we searched the Scopus database for conference proceedings and other reports. We reviewed the reference lists of relevant articles and related systematic reviews to identify original articles that we might have missed. We also searched ClinicalTrials.gov and the U.S. Food and Drug Administration Web site. Appendix Table. Detailed Search Strategy Study Selection We included studies of patients of all ages. We identified observational and randomized, controlled trials (RCTs) that included administration of N-acetylcysteine, sodium bicarbonate, sodium chloride, statins, or ascorbic acid to prevent CIN. The study groups received IOCM or LOCM via IV or IA injection, CIN outcome was explicitly defined, and sufficient data were reported to calculate the primary effect measure (relative risk reduction of CIN). Secondary outcomes included the need for renal replacement therapy, cardiac events, and mortality. We included only RCTs for the meta-analyses. All data from other studies and other strategies to reduce CIN incidence (such as adenosine antagonists, renal replacement therapy, diuretics, antioxidants, and vasoactive agents) were analyzed and included in the full report (12). We excluded studies of high-osmolar contrast medium because it is no longer used in clinical practice in the United States. We did not contact the authors for original data. Data Extraction and Quality Assessment Two reviewers independently screened the titles and abstracts for eligibility and independently assessed each studys risk of bias by using 5 items from the Cochrane Risk of Bias Tool for RCTs (3). We solved disagreements by consensus or a third reviewer when consensus was not possible. At random intervals during screening, we did quality checks to ensure that eligibility criteria were applied consistently. The second reviewer checked the accuracy of the data extracted by the first reviewer. We graded the strength of evidence (SOE) on comparisons of interest for the key outcomes by using the grading scheme recommended in the Methods Guide of the Evidence-based Practice Center and considered the domains of study limitations, directness, consistency, precision, reporting bias, and magnitude of effect (13). Following the guidance of the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) Working Group (14), we rated evidence as precise if the total number of patients exceeded an optimum information size and the 95% CI excluded a risk ratio (RR) of 1.0. If the number of patients exceeded the optimum information size and the CI did not exclude the possibility of no difference (that is, RR of 1.0), we only rated the evidence as precise if the CI excluded the possibility of a clinically important benefit or harm (that is, RR <0.75 or >1.25). We classified the SOE pertaining to each comparison into 4 category grades (high, moderate, low, and insufficient) and assigned SOE grades by group consensus. The body of evidence was considered high-grade if study limitations were low and there were no problems in any other domain, and it was subsequently downgraded for each domain in which a problem was identified. If the magnitude of effect was very large, the SOE could be upgraded. Data Synthesis and Analysis The primary outcome was CIN, defined as an increase in serum creatinine levels of more than 25% or 44.2 mol/L (0.5 mg/dL) within 3 days of intravascular administration of contrast media. We calculated individual study RRs and CIs and then obtained overall and subgroup summary RRs by using a random-effects model. For large comparisons with 18 or more studies, we used the DerSimonianLaird random-effects estimator, with the estimate of heterogeneity taken from the inverse-variance, fixed-effect model (15). Although this method is often the standard estimator used by many meta-analysis software programs, it tends to underestimate CIs when fewer than 18 studies are compared (15). To compensate, we used the KnappHartung small-sample estimator approach for comparisons with fewer than 18 studies. This method allows for small sample adjustments to the variance estimates and calculates CIs on the basis of the t distribution with k 1 degrees of freedom (15). We used the Harbord modified test for small study effects to determine whether there was asymmetry in effect estimates. To assess the clinical importance of differences in CIN incidence, a binary outcome, we followed guidance for selecting a minimally important difference on the basis of the overall event rate in the studies (14). Our clinical experts decided that a relative risk reduction of 25% would be clinically important, which is consistent with the guidance that suggests a reduction of 20% to 30% in determining optimal information size. To account for factors that could be associated with a difference in CIN risk, we did a subgroup analysis on the basis of the route of administration (IA vs. IV) and type of contrast media (IOCM vs. LOCM), baseline serum creatinine level, sex, age, and prevalence of diabetes mellitus. A priori, we assumed that there would be considerable heterogeneity and therefore used a random-effects model. We also examined the I 2, which measures the degree of heterogeneity across studies (I 2 varies from 0% to 100%, with 0% indicating no heterogeneity). All statistical analyses were done in Stata, version 13 (StataCorp). Role of the Funding Source The Agency for Healthcare Research and Quality selected the topic and assigned it to the Johns Hopkins University Evidence-based Practice Center. The Agency assigned a task order officer who provided comments on the protocol and draft versions of the full evidence report. The Agency did not directly participate in the literature search, determination of study eligibility, data analysis or interpretation, or preparation of the manuscript for publication. Results The literature search revealed 86 RCTs on interventions for preventing CIN (Appendix Figure). These study results were published between 1998 and 2015. Six studies were funded by industry sources (1621), 16 were funded by academia or government agencies, 33 had no funding statement, and the remainder reported no conflicts of interest. All findings from these studies were analyzed and described in the full report (12). Appendix Figure. Summary of evidence search and selection. CIN = contrast-induced nephropathy; RCT = randomized, controlled trial. * 24647 gray literature results were also found. Total does not sum to 371 because the 2 reviewers were not required to agree on reasons for exclusion. N-acetylcysteine Plus IV Saline Versus IV Saline N-acetylcysteine is a direct scavenger of free radicals and improves blood flow through nitric oxidemediated pathways, which results in vasodilatation. As a result, both the antioxidant and vasodilatory properties of N-acetylcysteine are believed to protect against CIN. We included 54 RCTs on N-acetylcysteine plus IV saline versus IV saline with or without a placebo published since 2002 in the meta-analysis (1669). The studies varied widely in patient and intervention characteristic

Validity of the Agency for Health Care Research and Quality Patient Safety Indicators and the Centers for Medicare and Medicaid Hospital-acquired Conditions: A Systematic Review and Meta-Analysis.

Based on accumulating evidence that the 3D topography and the chemical features of a growth surface influence neuronal differentiation, we combined these two features by evaluating the cytotoxicity, proliferation, and differentiation of the rat PC12 line and human neural stem cells (hNSCs) on chitosan (CS), cellulose acetate (CA), and polyethersulfone (PES)-derived electrospun nanofibers that had similar diameters, centered in the 200-500 nm range. None of the nanofibrous materials were cytotoxic compared to 2D (e.g., flat surface) controls; however, proliferation generally was inhibited on the nanofibrous scaffolds although to a lesser extent on the polysaccharide-derived materials compared to PES. In an exception to the trend toward slower growth on the 3D substrates, hNSCs differentiated on the CS nanofibers proliferated faster than the 2D controls and both cell types showed enhanced indication of neuronal differentiation on the CS scaffolds. Together, these results demonstrate beneficial attributes of CS for neural tissue engineering when this polysaccharide is used in the context of the defined 3D topography found in electrospun nanofibers.

Comparative Effect of Contrast Media Type on the Incidence of Contrast-Induced Nephropathy: A Systematic Review and Meta-analysis.

Background:The Agency for Health Care Research and Quality Patient Safety Indicators (PSIs) and Centers for Medicare and Medicaid Services Hospital-acquired Conditions (HACs) are increasingly being used for pay-for-performance and public reporting despite concerns over their validity. Given the potential for these measures to misinform patients, misclassify hospitals, and misapply financial and reputational harm to hospitals, these need to be rigorously evaluated. We performed a systematic review and meta-analysis to assess PSI and HAC measure validity. Methods:We searched MEDLINE and the gray literature from January 1, 1990 through January 14, 2015 for studies that addressed the validity of the HAC measures and PSIs. Secondary outcomes included the effects of present on admission (POA) modifiers, and the most common reasons for discrepancies. We developed pooled results for measures evaluated by ≥3 studies. We propose a threshold of 80% for positive predictive value or sensitivity for pay-for-performance and public reporting suitability. Results:Only 5 measures, Iatrogenic Pneumothorax (PSI 6/HAC 17), Central Line–associated Bloodstream Infections (PSI 7), Postoperative hemorrhage/hematoma (PSI 9), Postoperative deep vein thrombosis/pulmonary embolus (PSI 12), and Accidental Puncture/Laceration (PSI 15), had sufficient data for pooled meta-analysis. Only PSI 15 (Accidental Puncture and Laceration) met our proposed threshold for validity (positive predictive value only) but this result was weakened by considerable heterogeneity. Coding errors were the most common reasons for discrepancies between medical record review and administrative databases. POA modifiers may improve the validity of some measures. Conclusion:This systematic review finds that there is limited validity for the PSI and HAC measures when measured against the reference standard of a medical chart review. Their use, as they currently exist, for public reporting and pay-for-performance, should be publicly reevaluated in light of these findings.

Benefits and Harms of Osteoporosis Medications in Patients With Chronic Kidney Disease: A Systematic Review and Meta-analysis

Iodine contrast media are essential to many diagnostic and therapeutic procedures that involve imaging. An important potential side effect is contrast-induced nephropathy (CIN), most commonly defined in past studies as an increase in serum creatinine levels of more than 25% or 44.2 mol/L (0.5 mg/dL) within 3 days of intravascular contrast administration in the absence of an alternative cause (1). The precise mechanism of CIN is not entirely understood. The leading theories are that it results from hypoxic injury to the renal tubules induced by renal vasoconstriction or by direct cytotoxic effects of contrast media (2, 3); alternatively, some experts have arguedand recent evidence suggeststhat acute kidney injury occurring after intravascular contrast administration is caused by coexisting risk factors and is only coincidentally related to the contrast media, especially when administered intravenously (4, 5). Regardless of the cause, acute kidney injury after intravascular contrast administration remains a major concern for referring clinicians. Osmolality of contrast media is a key factor determining its tolerability (6). Since the 1990s, low-osmolar contrast media (LOCM) (2 to 3 times plasma osmolality) have been the standard of care for intravascular injection. A newer class of intravascular contrast, iso-osmolar contrast media (IOCM), is isotonic to plasma. Iodixanol is the only IOCM available for intravascular injection. The literature contains conflicting reports about whether iodixanol is associated with less risk for CIN than LOCM (7, 8). International guidelines from the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Work Group mention IOCM and LOCM, but they do not make recommendations about selection between them (9). We did a systematic review of randomized, controlled trials (RCTs) to determine the comparative effects of different types of intravascular contrast media on CIN risk in patients having diagnostic imaging studies or image-guided procedures. We hypothesized that updating past reviews with more recent RCTs may help us understand conflicting reports about CIN risk. Some reports suggest that intra-arterial administration may be associated with greater risk than intravenous administration (4, 10, 11), so we also investigated whether the comparative effects vary according to the route of administration. Methods We developed and followed a review protocol, which is included in the full technical report on which this article is based (12). Data Sources and Searches We searched (without date or language restrictions) PubMed, EMBASE, and the Cochrane Library for RCTs published through 30 June 2015, as well as the Scopus database for conference proceedings and other reports (Appendix Table 1). We also reviewed the reference lists of relevant articles and related systematic reviews, searched ClinicalTrials.gov to identify ongoing studies, and asked an external expert panel to identify trials missing from our final list of eligible articles. Appendix Table 1. Search Strategy Study Selection We selected all RCTs that compared 1 or more contrast media types (LOCM or IOCM) with CIN incidence as the main outcome in patients having diagnostic imaging or image-based therapeutic procedures. Studies had to report the incidence of CIN based on serum creatinine levels or glomerular filtration rates at baseline and within 72 hours of contrast injection. Studies could involve patients of any age and preprocedure risk for CIN. There were no restrictions on how the contrast classes were compared, so studies comparing different types of LOCM and those comparing LOCM with IOCM were included. Two reviewers independently screened titles and abstracts to identify articles for inclusion. If necessary, the full text of articles was reviewed. Articles in a language other than English were excluded at the full-text level. Discrepancies between the 2 reviewers that remained after full-text review were resolved by consensus. At random intervals during screening, quality checks were done to ensure that eligibility criteria were applied consistently. Data Extraction and Quality Assessment For each eligible study, 1 investigator extracted pertinent data about study characteristics, patient population, imaging procedure type, comparisons, results, and statistical analysis. A second investigator reviewed the extracted data for accuracy. Discrepancies between the 2 investigators were resolved by consensus. Article and data management were done within the DistillerSR Web service (Evidence Partners). Two reviewers independently assessed each studys risk of bias using the following 5 items from the Cochrane Risk of Bias Tool for randomized studies: allocation sequence generation, allocation concealment, investigator blinding, incomplete outcomes, and selective outcome reporting (13). Discrepancies were resolved by consensus. Data Synthesis and Analysis When evaluating changes in CIN risk, we followed published guidelines for selecting a minimally important clinical difference based on the overall observed event rate in the studies (14). Taking into consideration the potential effect of CIN on a patients overall health and well-being, the clinical experts on our team decided that a 25% reduction in the relative risk for CIN would be clinically important, which is consistent with the published guidance suggesting a range of reduction in relative risk of 20% to 30% in determining optimal information size (14). For each comparison in our review, the study team assigned a grade (high, moderate, low, or insufficient) for the strength of evidence (SOE) associated with the entire group of studies that represented the particular comparison. Grades for SOE were assigned by consensus of the senior study team members (J.E., R.W., R.S., and E.B.). This grading scheme considered all of the following domains in the Agency for Healthcare Research and Quality guidelines for comparative effectiveness reviews: study limitations, precision, directness, consistency, reporting bias, and magnitude of effect (15). The study limitations domain was assessed by examining the risk-of-bias items for each study involved in the comparison. Study limitations were considered high if more than half of the studies in a group scored negatively in at least 1 of the risk-of-bias items, low if more than half of the studies in the group scored positively in all 5 risk-of-bias items, or medium if neither the high nor the low criteria were met. The precision domain was assessed by following guidance from the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group (14). We rated a group of studies as precise if the total number of patients exceeded the optimum information size (14) and the 95% CI excluded a pooled relative risk of 1.0. If the total number of patients exceeded the optimum information size but the CI did not exclude a relative risk of 1.0, we only rated the evidence as precise if the CI excluded the possibility of a 25% minimally important clinical difference as defined previously (relative risk <0.75 or >1.25). For the main outcome of interest, CIN, we calculated an optimum information size of 2000 patients based on an expected 0.1 probability of CIN and a minimally important relative risk of less than 0.75 or greater than 1.25. The SOE of a group of studies was graded high if the study limitations domain was considered low and all other SOE domains were scored positively. The SOE was downgraded for each domain that was scored negatively. If the magnitude of effect was very large, the SOE was upgraded. We did de novo meta-analyses of all studies on a given comparison if study heterogeneity was not important by clinical, qualitative, and statistical criteria (16). We calculated pooled risks by using a random-effects model and the DerSimonianLaird method (17). We used a funnel plot and the Harbord modified test for small study effects (18) to look for asymmetry in the reporting of results, which can be seen when publication bias exists. Analyses were done in Stata, version 13 (StataCorp). Role of the Funding Source The Agency for Healthcare Research and Quality selected the review topic and funded this research under a contract. A representative from the Agency provided technical assistance during creation of the full evidence report on which this article is based and provided comments on draft versions of that report (12). The Agency did not directly participate in the literature search; determination of study eligibility criteria; data collection, analysis, or interpretation; or preparation, review, or approval of the manuscript for publication. Results The literature search revealed 29 RCTs for summary and analysis (Figure 1). Five RCTs compared 2 or more types of LOCM in 826 patients (Appendix Table 2) (1923). Twenty-five RCTs compared the IOCM iodixanol with 1 or more types of LOCM in 5053 patients (Appendix Table 2) (19, 2447). One RCT reported data on both types of comparisons (19). In the 5 RCTs that compared LOCM, 4 studies scored negatively in 1 or more of the 5 risk-of-bias items (Appendix Table 3). In the 25 RCTs comparing iodixanol and LOCM, all studies scored negatively in 1 or more of the 5 risk-of-bias items (Appendix Table 4). Of the 29 RCTs included in our review, 14 (48%) studies (19, 20, 29, 3338, 4043, 45) received funding support from industry sources, all of which were contrast media manufacturers. Figure 1. Summary of evidence search and selection. * Sum of reasons for exclusion exceeds 443 because reviewers were not required to agree on the reason. Appendix Table 2. Study Characteristics Appendix Table 3. Risk of Bias for RCTs Comparing LOCMs* Appendix Table 4. Risk of Bias for RCTs Comparing Iodixanol and LOCMs* No study comparing 2 LOCM reported a statistically significant or clinically important difference between study groups in the incidence of CIN or a related measure of renal func

Patient perspectives of care and process and outcome quality measures for heart failure admissions in US hospitals: how are they related in the era of public reporting?

In 2012, about 11% to 15% of U.S. adults were estimated to have chronic kidney disease (CKD) (13). One complication of CKD is mineral and bone disorder (MBD). In its 2009 guideline, Kidney Disease: Improving Global Outcomes (KDIGO) defined CKDMBD as a systemic disorder of mineral and bone metabolism resulting from CKD (4). The disorder is characterized by any of the following in a patient with CKD: 1) calcium, phosphorus, parathyroid hormone, or vitamin D metabolism abnormalities; 2) bone turnover, mineralization, volume linear growth, or strength abnormalities; or 3) extraskeletal calcification. If untreated, CKDMBD can lead to weak and brittle bones and fractures in adults and bone deformities in children. Within the first year after kidney transplantation, patients experience a rapid loss of bone, often due to preexisting bone disease and immunosuppressive medications (5). Patients with CKD, particularly those with end-stage renal disease and those requiring kidney transplantation, have a higher risk for fractures than the general population (610). Fractures are associated with reduced quality of life and higher mortality (1115). In its previous guidelines, KDIGO recommended that patients with stage 1 to 2 CKD and osteoporosis and/or high risk for fracture be treated with bisphosphonates, teriparatide, or raloxifene and managed similarly to the general population (4). In 2013, KDIGO identified this recommendation as needing an update (16). Earlier studies were limited to post hoc analyses of trials and were not generalizable to patients with the biochemical abnormalities of CKDMBD. Several clinical trials evaluating therapies other than bisphosphonates have recently been published, and a new therapy (denosumab) for treatment of osteoporosis is now available. In this systematic review, we update evidence on the efficacy and safety of osteoporosis medications, including bisphosphonates, teriparatide, raloxifene, and denosumab, among patients with CKD. Methods This article is part of a larger review to update the evidence supporting recommendations identified for updating by the KDIGO Controversies Conference. On the basis of the results of this conference, we formulated research questions for a systematic review that could inform an update of the guideline. With input from the guideline chairs, we developed a document (available from the authors on request) that outlined the relevant population, intervention, comparisons, outcomes, and study designs for each research question. We followed the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines (17). Data Sources and Searches We searched PubMed and the Cochrane Central Register of Controlled Trials from December 2006 through December 2016. The start date was chosen to allow a 1-year overlap with the search in the prior review (4). The search strategy included Medical Subject Headings and text terms for CKD and the interventions and markers of interest (Appendix Table 1) and was limited to English-language studies. We rereviewed the studies included in the 2009 guideline. We also reviewed the list of references that were suggested during the KDIGO Controversies Conference. Appendix Table 1. PubMed Search Strategy Study Selection Two reviewers independently screened titles and abstracts and full-text articles for inclusion. We resolved differences on inclusion through consensus adjudication. We included English-language, randomized, controlled trials that compared bisphosphonates, teriparatide, denosumab, or raloxifene with placebo, usual care, or an active control. We placed no restrictions on the dose or formulation of the therapies. All trials must have included or had a subgroup analysis of patients with stage 3 to 5 CKD, patients receiving dialysis, or kidney transplant recipients. There were no restrictions on how CKD was diagnosed. All trials had to have followed at least 25 patients for at least 6 months. We included trials that evaluated bone mineral density (BMD), incident fractures, or adverse events (death, cardiovascular disease events, infections, renal adverse events, musculoskeletal pain, hypercalcemia, hypocalcemia, hyperphosphatemia, hypophosphatemia, hypersensitivity reactions, gastrointestinal adverse events, and osteonecrosis of the jaw). Data Abstraction and Quality Assessment One reviewer abstracted data, with confirmation from a second reviewer. We abstracted data on general study characteristics; funding source; participant characteristics; interventions and co-interventions; and outcome measures, including measures of variability. Two reviewers independently assessed risk of bias of each study by using the Cochrane Collaborations tool (18). Disagreements were resolved through discussion. Data Synthesis and Analysis We created a set of detailed evidence tables. We conducted meta-analyses when we deemed that data from at least 2 trials were sufficiently homogeneous with respect to the following key variables: population characteristics, study duration, and medication dosing. Separate analyses were conducted for the different CKD patient populations (patients with stage 3 to 5 disease, patients receiving dialysis, and transplant recipients). We used a random-effects model with the KnappHartung method (19) to pool odds ratios (ORs). This method was chosen because it accounts for the small number of studies when variance is being estimated (20). We used the treatment group continuity correction (the inverse of the sample size in the opposite treatment group in cells with 0 events) when there were no events (21). The I 2 statistic was used to evaluate statistical heterogeneity among trials (22). We explored publication bias by using the Begg and Mazumdar test (23) and the Egger test (24) when there were at least 10 studies for a given analysis. In a sensitivity analysis, we pooled the ORs using a DerSimonianLaird random-effects model (25). Although this model is commonly used, it estimates CIs that may be too narrow (20). All statistical analyses were conducted using Stata, version 14.2 (StataCorp). Meta-analysis files are available from the authors on request. Grading of the Evidence We adapted the GRADE (Grading of Recommendations Assessment, Development and Evaluation) scheme to assess the strength of evidence (SOE) for each comparison for BMD and fractures. Two reviewers independently graded the studies in terms of risk of bias, consistency, directness, and other limitations. The final SOE grades were high, moderate, low, or very low. The guideline work group met with the evidence review team to review the evidence grading. Role of the Funding Source KDIGO suggested the research questions and reviewed the draft evidence tables and report but had no role in the literature search, determination of study eligibility, analysis, or preparation of the manuscript for publication. Results Search Results We retrieved 13692 records from our search (Figure). After reviewing the abstracts and full texts, we included 13 studies that evaluated a bisphosphonate, teriparatide, raloxifene, or denosumab in terms of BMD or fractures among a total of 9850 patients with CKD (2638). We identified 8 new studies for this update (27, 2932, 3638); the other 5 were identified in the previous review (26, 28, 3335). Figure. Summary of search and review process. CKD= chronic kidney disease; RCT= randomized, controlled trial. Study Characteristics Table 1 provides details on the study design and participant characteristics of the included studies. Nine studies were randomized, controlled trials among kidney transplant recipients (26, 27, 30, 31, 37, 38), patients with stage 3 to 5 CKD (29, 32), or patients receiving dialysis (32, 33). Four studies were subgroup analyses of patients with CKD conducted in randomized, controlled trials of postmenopausal women (28, 3436). There was 1 head-to-head trial comparing 2 different bisphosphonates (38); the other trials were placebo-controlled. Patients in most studies were given concomitant calcium or vitamin D supplements or both (26, 27, 2931, 34, 35, 37, 38). The study durations ranged from 8 to 36 months. Table 1. Characteristics of Randomized, Controlled Trials Evaluating Bisphosphonates and Other Osteoporosis Medications Among Patients With CKD Five studies included only women (28, 32, 3436). All of the studies were conducted in adults, and the mean age of participants ranged from 44 to 80 years. Mean serum calcium levels (reported in 10 studies) ranged from 2.0 to 2.5 mmol/L (7.9 to 9.9 mg/dL), and mean serum phosphorus levels (reported in 7 studies) ranged from 0.6 to 2.2 mmol/L (1.8 to 6.9 mg/dL). Lumbar spine and femoral neck BMD scores were generally low at baseline. One study excluded patients with diabetes (38). The percentage of patients with diabetes ranged from 3% to 60% in the 2 studies that reported on this (29, 34). Risk of Bias We rated studies as having moderate to high risk of bias (Appendix Table 2). Only 1 study described blinding of participants and study personnel (30), but 7 described blinding of the radiologists assessing the outcomes (2631, 35). Most studies did not report adequate details about sequence generation or allocation concealment or had incomplete outcome reporting. Three studies referenced their ClinicalTrials.gov registry entry and reported on all outcomes listed in the registry (29, 30, 37). Most of the trials either received industry funding (27, 2931, 33, 35, 36) or did not report their funding source (26, 28, 32, 34, 38). One study was funded exclusively by nonprofit organizations (37). Appendix Table 2. Risk of Bias of Randomized, Controlled Trials Evaluating Bisphosphonates and Other Osteoporosis Medications Among Patients With Chronic Kidney Disease BMD Bisphosphonates Versus Placebo Six studies (n= 1013) with moderate risk of bias and 12 to 36 months of follow-up compared a bisphosphonate with placebo in terms of BMD (2631). We were unable to c

Patient- and Caregiver-Reported Assessment Tools for Palliative Care: Summary of the 2017 Agency for Healthcare Research and Quality Technical Brief

IMPORTANCE Process quality measure performance has improved significantly with public reporting, requiring reevaluation of process-outcome relationships and the emerging role of patient perspectives on care. OBJECTIVE To evaluate associations between heart failure patient perspectives of care and publicly reported processes and outcomes. DESIGN Cross-sectional study, July 2008-June 2011. SETTING US hospitals in the Press Ganey database. PARTICIPANTS Heart failure inpatients. MEASURES Outcomes were Hospital Compare hospital-level risk-adjusted 30-day heart failure mortality and readmissions. Predictors included Hospital Compare heart failure processes of care, a weighted process composite and Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) domains for heart failure. Hospital characteristics included volume of heart failure patients and race, health status and education. RESULTS Among 895 included hospitals, performance on process measures was high (median by hospital for composite, 95.6%); the median HCAHPS overall rating was 86.9. Median mortality was 11.3% and readmissions was 24.8%. No process measures were statistically significantly associated with lower mortality or readmissions in adjusted analyses. Higher ratings on HCAHPS patient perspectives of care were significantly correlated with lower readmissions in adjusted analyses, particularly those publicly reported domains conceptually related to readmissions. The magnitude was small (1.8 points higher on a 100-point scale between the highest and lowest quartiles of hospital readmissions). CONCLUSIONS Publicly reported process quality measures were no longer associated with outcomes, but higher patient perspectives of care were associated with lower heart failure readmissions. These associations support continued reevaluation of these measures and increased emphasis on patient experience and outcomes, as planned for Value-Based Purchasing.

Data Linkage Strategies to Advance Youth Suicide Prevention: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop.

CONTEXT Assessment tools are data collection instruments that are completed by or with patients or caregivers and which collect data at the individual patient or caregiver level. OBJECTIVES The objectives of this study are to 1) summarize palliative care assessment tools completed by or with patients or caregivers and 2) identify needs for future tool development and evaluation. METHODS We completed 1) a systematic review of systematic reviews; 2) a supplemental search of previous reviews and Web sites, and/or 3) a targeted search for primary articles when no tools existed in a domain. Paired investigators screened search results, assessed risk of bias, and abstracted data. We organized tools by domains from the National Consensus Project Clinical Practice Guidelines for Palliative Care and selected the most relevant, recent, and highest quality systematic review for each domain. RESULTS We included 10 systematic reviews and identified 152 tools (97 from systematic reviews and 55 from supplemental sources). Key gaps included no systematic review for pain and few tools assessing structural, cultural, spiritual, or ethical/legal domains, or patient-reported experience with end-of-life care. Psychometric information was available for many tools, but few studies evaluated responsiveness (sensitivity to change) and no studies compared tools. CONCLUSION Few to no tools address the spiritual, ethical, or cultural domains or patient-reported experience with end-of-life care. While some data exist on psychometric properties of tools, the responsiveness of different tools to change and/or comparisons between tools have not been evaluated. Future research should focus on developing or testing tools that address domains for which few tools exist, evaluating responsiveness, and comparing tools.

Low escape-rate genome safeguards with minimal molecular perturbation of Saccharomyces cerevisiae

In 2014, suicide was the second leading cause of death in the United States among persons between the ages of 15 to 19 and 20 to 29 years (1). Suicide rates increased by 24% from 1999 through 2014, and the percentage increase in suicide rates was greatest for females aged 10 to 14 years (2). It is difficult to evaluate the longer-term effect of prevention efforts that may be applied years before the peak period of risk for suicidal behaviors. Unanswered questions remain about the effectiveness of youth suicide prevention efforts, in part because of the difficulty associated with long-term follow-up of large populations. Data systems comprise collections of information plus the information technology infrastructure required to operate, maintain, and access the systems. They can be organized in various forms and include electronic health records, payer claims databases, vital records, periodic population surveys, and health information exchanges. Data systems exist for various purposes, including surveillance, billing, and administration of services. The linkage of existing data from prevention studies to data systems that include suicidal behavior outcomes could help identify which interventions are most effective in preventing suicide. The aim of this project was to provide an objective description of the state of the science on data linkage strategies in suicide prevention research, as well as a systematic summary of ongoing research limitations, barriers, gaps, and opportunities for future data linkage approaches to enhance suicide prevention efforts. Methods Detailed methods, including the full set of key questions, analytic framework, search strategies, inclusion criteria, and study data extraction, are available in the full Evidence-based Practice Center report (3). A protocol was developed in September 2015 and is provided in Supplement 1. This article addresses the following question: What national, state, and community data systems can be linked to existing data from prevention efforts in order to add possible value for stakeholders? Supplement 1. Evidence-based Practice Center Systematic Review Protocol Data Sources and Searches We conducted 3 parallel searches to identify suicide prevention studies and relevant data systems. We performed a systematic review of published literature to identify prevention studies, existing suicide data systems, and publications in which the two had been linked; we conducted an environmental scan to identify suicide data systems not reported in the published literature; and we performed a targeted search to identify suicide data systems used in selected states, cities, and communities. Systematic Review of Prevention Studies We searched PubMed, the Cochrane Library, the Campbell Collaboration Library of Systematic Reviews, CINAHL, PsycINFO, and ERIC (Education Resources Information Center) for articles published from January 1990 to December 2015. The search strategies we used are provided in Appendix Table 1. Appendix Table 1. Detailed Search Strategies Data Systems We scanned all studies identified in the systematic literature search for data systems. We then conducted an environmental scan to identify additional data systems not reported in the published literature. Because data systems are usually developed and maintained for operational rather than research purposes, they are often not described in peer-reviewed publications that are the subject of systematic reviews. Finding data systems requires environmental scans, also known as searching the gray literature, which comprises preprints, preliminary progress and advanced reports, technical reports, statistical reports, memoranda, state-of-the-art reports, market research reports, theses, conference proceedings, technical specifications and standards, noncommercial translations, bibliographies, technical and commercial documentation, and official documents not published commercially (primarily government reports and documents) (4). We used the advanced search functions of 3 search engines (Google, Yahoo, and Bing [Microsoft]) to execute the search. We also searched the Web sites of the American Foundation for Suicide Prevention, the American Association of Suicidology, and the Suicide Prevention Resource Center. Targeted Search We conducted a targeted search in 6 states (California, Delaware, Oregon, Illinois, Maryland, and Wisconsin), 2 cities (Baltimore, Maryland, and Wilmington, Delaware), and 1 tribal community (the Menominee Reservation in Wisconsin) for data systems that provided information about our primary outcomes (suicidal ideation, suicide attempt, and suicide) and that were maintained by a state-, city-, or community-level entity. We contacted (via e-mail and telephone) persons in each target area who were responsible for suicide prevention and other public health efforts to request information on state- and community-level sources or systems that included data on suicidal ideation, suicide attempt, and suicide among persons younger than 26 years. Study Selection Systematic Review of Suicide Prevention Studies Two investigators independently reviewed titles and abstracts and then full-text articles using prespecified eligibility criteria. We included studies of humans aged 0 to 25 years with at least 1 intervention and at least 1 outcome of interest (suicide, suicide attempt, or suicidal ideation). Meeting abstracts, articles without original data, and studies conducted outside the United States and not written in English were excluded. We did not limit inclusion by population size or design. Studies published before 1990 were not included; according to the National Action Alliance for Suicide Prevention, suicide became a central issue in the United States in the mid-1990s with the publication by the U.S. Department of Health and Human Services of the Report of the Secretarys Task Force on Youth Suicide in 1989 and the Surgeon Generals Call to Action to Prevent Suicide in 1999 (5). In addition, the amount of abstractable data is significantly limited before 1990. Disagreements about article eligibility that could not be resolved by the 2 reviewers were resolved by the domain experts on the team. Data Systems Two independent experts reviewed the results of the systematic review and environmental scan and determined whether identified data systems met the same eligibility criteria as those applied in the systematic review (other than having to include data about an intervention) and whether they fulfilled the minimum requirements of a data system that can be useful for linkage to suicide prevention studies. We excluded data systems that did not meet all of the following requirements: 1) the data system still exists, and underlying data are available and accessible in digital format; 2) the data system can be shared and acquired by others for research purposes; 3) the data system collects and contains information on at least 1 of the primary outcomes; and 4) the data system is not a duplicate. Data Extraction and Quality Assessment Systematic Review of Suicide Prevention Studies We abstracted data on study, participant, and intervention characteristics as well as suicide outcomes to Microsoft Excel tables. We also abstracted the primary analytic method used by the study, linkage to data systems (if present), and statistical tests used in the study and controlled for covariates. We identified and abstracted data system information (for example, location of the database) and how the data were linked to other sources. Data Systems A coding and classification schema previously used for evaluating community-based data systems was used to classify data system quality and accessibility, including whether data dictionaries and data were readily available (6). We sought additional information about the data systems by searching the Internet for data dictionaries and documentation associated with the data system, downloading a sample data set from the data system, and searching for additional reports that may have described the data system in more detail. Role of the Funding Source The Agency for Healthcare Research and Quality (AHRQ) funded the review, and a working group convened by the National Institutes of Health assisted in developing the scope of the review and the key questions. Neither organization had a role in study selection, quality assessment, or synthesis. The investigators are solely responsible for the content. Results Suicide Prevention Studies The literature search identified 47 studies (reported in 59 articles) (Figure 1). Study population size was highly variable, ranging from 32 to 2100. Twenty-nine of the studies (62%) had 500 or fewer participants. One third (34%) of the prevention intervention studies we identified reported on outcomes more than 1 year after the intervention. Ten studies (21%) focused on special populations, including military personnel (710), incarcerated persons (1113), survivors of sexual trauma (14), persons with major depressive disorder (15), and high-risk youth (16). The 47 studies used various interventions and prevention approaches, and many applied more than 1 prevention approach, such as behavioral and skill building (17 studies), medication or pharmaceutical (7 studies), psychotherapy (10 studies), educational and skill building (12 studies), policy (3 studies), screening (5 studies), and other approaches (9 studies) (Appendix Table 2). Figure 1. Summary of evidence search and selection. ERIC= Education Resources Information Center. * Searched simultaneously through the EBSCO database. Sum of individual reasons exceeds total number of exclusions because reviewers were not required to agree on reason for exclusion. Appendix Table 2. Summary of Intervention Characteristics Data Systems Our literature search, environmental scan, and targeted geographic searches identified 153 unique data systems (Figure 2; Supplement 2). Seven data systems were found in articles

Assessment tools for palliative care.

Significance As the use of synthetic biology grows, there is an increasing need to ensure biocontainment both to protect engineered proprietary strains and to mitigate potential inadvertent or advertent release to the environment. Here, we screen for the best-performing construct for essential gene-dependent transcriptional safeguards (SGs) in yeast. We have engineered strains that have near-WT fitness and a low escape rate, and grow in the presence of a nanomolar concentration of essential supplement. We also improved our “safeguard” construct by promoter engineering, as well as by analyzing a series of potential “decoy molecules” that could be used to mask the existence of critical chemical ligands required to grow the SG strain. As the use of synthetic biology both in industry and in academia grows, there is an increasing need to ensure biocontainment. There is growing interest in engineering bacterial- and yeast-based safeguard (SG) strains. First-generation SGs were based on metabolic auxotrophy; however, the risk of cross-feeding and the cost of growth-controlling nutrients led researchers to look for other avenues. Recent strategies include bacteria engineered to be dependent on nonnatural amino acids and yeast SG strains that have both transcriptional- and recombinational-based biocontainment. We describe improving yeast Saccharomyces cerevisiae-based transcriptional SG strains, which have near-WT fitness, the lowest possible escape rate, and nanomolar ligands controlling growth. We screened a library of essential genes, as well as the best-performing promoter and terminators, yielding the best SG strains in yeast. The best constructs were fine-tuned, resulting in two tightly controlled inducible systems. In addition, for potential use in the prevention of industrial espionage, we screened an array of possible “decoy molecules” that can be used to mask any proprietary supplement to the SG strain, with minimal effect on strain fitness.