A Case of Acute Decompensated Heart Failure Complicated by Cardiorenal Syndrome Treated With Ultrafiltration.

The standard of care of treatment for acute decompensated heart failure (ADHF) complicated by cardiorenal syndrome (CRS) is diuretics. This case report is an example of how the institution of ultrafiltration early in the course of ADHF complicated by CRS for volume removal can be an alternative approach rather than escalation of the diuretic regimen when the initial diuretic regimen is ineffective and, in turn, yielding a good clinical course.

Medications Affecting the Biochemical Conversion to Type 2 Diabetes: A Systematic Review and Meta-Analysis.

CONTEXT: The extent to which some pharmacological interventions reduce or increase the risk of biochemical conversion to type 2 diabetes mellitus (T2DM) in at-risk individuals is unclear. METHODS: We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus through 24 August 2017 for randomized controlled trials evaluating the effect of drugs suspected to modify the risk of biochemical conversion to T2DM. RESULTS: We included 43 trials with 192,156 subjects (mean age, 60 years; 56% men; mean body mass index, 30.4 kg/m2). α-Glucosidase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, metformin, orlistat, phentermine/topiramate, and pioglitazone significantly reduced the risk of biochemical conversion to T2DM, whereas statins and nateglinide increased the risk. There was insufficient direct evidence regarding the effects of sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Most trials were brief and evaluated this outcome during treatment without a withdrawal or washout period. CONCLUSIONS: Several drugs modify the risk of biochemical conversation to T2DM, although whether this effect is persistent and clinically relevant is unclear. Future studies need to focus on cardiovascular disease prevention, mortality, and patient-important outcomes instead of biochemical conversion to T2DM.

Histone H3K27 Trimethylation Modulates 5-Fluorouracil Resistance by Inhibiting PU.1 Binding to the DPYD Promoter.

The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) is a major determinant of 5-FU response and toxicity. Although DPYD variants may affect 5-FU metabolism, they do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Here, we report that H3K27 trimethylation (H3K27me3) at the DPYD promoter regulated by Ezh2 and UTX suppresses DPYD expression by inhibiting transcription factor PU.1 binding, leading to increased resistance to 5-FU. Enrichment of H3K27me3 at the DPYD promoter was negatively correlated with both DPYD expression and DPD enzyme activity in peripheral blood specimens from healthy volunteers. Lastly, tumor expression data suggest that DPYD repression by Ezh2 predicts poor survival in 5-FU-treated cancers. Collectively, the findings of the present article suggest that a previously uncharacterized mechanism regulates DPD expression and may contribute to tumor resistance to 5-FU. Cancer Res; 76(21); 6362-73. ©2016 AACR.

A systematic review and meta-analysis of tests to predict wound healing in diabetic foot.

BACKGROUND: This systematic review summarized the evidence on noninvasive screening tests for the prediction of wound healing and the risk of amputation in diabetic foot ulcers. METHODS: We searched MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Scopus from database inception to October 2011. We pooled sensitivity, specificity, and diagnostic odds ratio (DOR) and compared test performance. RESULTS: Thirty-seven studies met the inclusion criteria. Eight tests were used to predict wound healing in this setting, including ankle-brachial index (ABI), ankle peak systolic velocity, transcutaneous oxygen measurement (TcPo2), toe-brachial index, toe systolic blood pressure, microvascular oxygen saturation, skin perfusion pressure, and hyperspectral imaging. For the TcPo2 test, the pooled DOR was 15.81 (95% confidence interval [CI], 3.36-74.45) for wound healing and 4.14 (95% CI, 2.98-5.76) for the risk of amputation. ABI was also predictive but to a lesser degree of the risk of amputations (DOR, 2.89; 95% CI, 1.65-5.05) but not of wound healing (DOR, 1.02; 95% CI, 0.40-2.64). It was not feasible to perform meta-analysis comparing the remaining tests. The overall quality of evidence was limited by the risk of bias and imprecision (wide CIs due to small sample size). CONCLUSIONS: Several tests may predict wound healing in the setting of diabetic foot ulcer; however, most of the available evidence evaluates only TcPo2 and ABI. The overall quality of the evidence is low, and further research is needed to provide higher quality comparative effectiveness evidence.

A systematic review and meta-analysis of glycemic control for the prevention of diabetic foot syndrome.

OBJECTIVE: The objective of this review was to synthesize the available randomized controlled trials (RCTs) estimating the relative efficacy and safety of intensive vs less intensive glycemic control in preventing diabetic foot syndrome. METHODS: We used the umbrella design (systematic review of systematic reviews) to identify eligible RCTs. Two reviewers determined RCT eligibility and extracted descriptive, methodologic, and diabetic foot outcome data. Random-effects meta-analysis was used to pool outcome data across studies, and the I(2) statistic was used to quantify heterogeneity. RESULTS: Nine RCTs enrolling 10,897 patients with type 2 diabetes were included and deemed to be at moderate risk of bias. Compared with less intensive glycemic control, intensive control (hemoglobin A1c, 6%-7.5%) was associated with a significant decrease in risk of amputation (relative risk [RR], 0.65; 95% confidence interval [CI], 0.45-0.94; I(2) = 0%). Intensive control was significantly associated with slower decline in sensory vibration threshold (mean difference, -8.27; 95% CI, -9.75 to -6.79). There was no effect on other neuropathic changes (RR, 0.89; 95% CI, 0.75-1.05; I(2) = 32%) or ischemic changes (RR, 0.92; 95% CI, 0.67-1.26; I(2) = 0%). The quality of evidence is likely moderate. CONCLUSIONS: Compared with less intensive glycemic control therapy, intensive control may decrease the risk of amputation in patients with diabetic foot syndrome. The reported risk reduction is likely overestimated because the trials were open and the decision to proceed with amputation could be influenced by glycemic control.

A systematic review and meta-analysis of débridement methods for chronic diabetic foot ulcers.

BACKGROUND: Several methods of débridement of diabetic foot ulcers are currently used. The relative efficacy of these methods is not well established. METHODS: This systematic review and meta-analysis was conducted to find the best available evidence for the effect of débridement on diabetic foot wound outcomes. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2011 for randomized controlled studies (RCTs) and observational comparative studies. RESULTS: We identified 11 RCTs and three nonrandomized studies reporting on 800 patients. The risk of bias was moderate overall. Meta-analysis of three RCTs showed that autolytic débridement significantly increased the healing rate (relative risk [RR], 1.89; 95% confidence interval [CI] 1.35-2.64). Meta-analysis of four studies (one RCT) showed that larval débridement reduced amputation (RR, 0.43; 95% CI, 0.21-0.88) but did not increase complete healing (RR, 1.27; 95% CI, 0.84-1.91). Surgical débridement was associated with shorter healing time compared with conventional wound care (one RCT). Insufficient evidence was found for comparisons between autolytic and larval débridement (one RCT), between ultrasound-guided and surgical débridement, and between hydrosurgical and surgical débridement. CONCLUSIONS: The available literature supports the efficacy of several débridement methods, including surgical, autolytic, and larval débridement. Comparative effectiveness evidence between these methods and supportive evidence for other methods is of low quality due to methodologic limitations and imprecision. Hence, the choice of débridement method at the present time should be based on the available expertise, patient preferences, the clinical context and cost.

A systematic review and meta-analysis of adjunctive therapies in diabetic foot ulcers.

BACKGROUND: Multiple adjunctive therapies have been proposed to accelerate wound healing in patients with diabetes and foot ulcers. The aim of this systematic review is to summarize the best available evidence supporting the use of hyperbaric oxygen therapy (HBOT), arterial pump devices, and pharmacologic agents (pentoxifylline, cilostazol, and iloprost) in this setting. METHODS: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2011. Pairs of independent reviewers selected studies and extracted data. Predefined outcomes of interest were complete wound healing and amputation. RESULTS: We identified 18 interventional studies; of which 9 were randomized, enrolling 1526 patients. The risk of bias in the included studies was moderate. In multiple randomized trials, the addition of HBOT to conventional therapy (wound care and offloading) was associated with increased healing rate (Peto odds ratio, 14.25; 95% confidence interval, 7.08-28.68) and reduced major amputation rate (odds ratio, 0.30; 95% confidence interval, 0.10-0.89), compared with conventional therapy alone. In one small trial, arterial pump devices had a favorable effect on complete healing compared with HBOT and in another small trial compared with placebo devices. Neither iloprost nor pentoxifylline had a significant effect on amputation rate compared with conventional therapy. No comparative studies were identified for cilostazol in diabetic foot ulcers. CONCLUSIONS: There is low- to moderate-quality evidence supporting the use of HBOT as an adjunctive therapy to enhance diabetic foot ulcer healing and potentially prevent amputation. However, there are only sparse data regarding the efficacy of arterial pump devices and pharmacologic interventions.

A systematic review and meta-analysis of off-loading methods for diabetic foot ulcers.

BACKGROUND: Increased plantar foot pressure is one of several key factors that lead to diabetic foot ulcers. Multiple methods have been proposed to relieve this pressure and thus enhance wound healing and potentially prevent relapse. We aimed in this systematic review to find the best available evidence for off-loading methods. METHODS: We searched MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and Scopus through October 2011. Pairs of independent reviewers selected studies and extracted data. Predefined outcomes of interest included complete wound healing, time to complete wound healing, amputation, infection, and relapse rates. RESULTS: We identified 19 interventional studies, of which 13 were randomized controlled trials, including data from 1605 patients with diabetic foot ulcers using an off-loading method. The risk of bias in the included studies was moderate. This analysis demonstrated improved wound healing with total contact casting over removable cast walker, therapeutic shoes, and conventional therapy. There was no advantage of irremovable cast walkers over total contact casting. There was improved healing with half-shoe compared with conventional wound care. Therapeutic shoes and insoles reduced relapse rate in comparison with regular footwear. Data were sparse regarding other off-loading methods. CONCLUSIONS: Although based on low-quality evidence (ie, evidence warranting lower certainty), benefits are demonstrated for use of total contact casting and irremovable cast walkers in the treatment of diabetic foot ulcers. Reduced relapse rate is demonstrated with various therapeutic shoes and insoles in comparison with regular footwear.

PREDICTORS OF BIOCHEMICAL REMISSION AND RECURRENCE AFTER SURGICAL AND RADIATION TREATMENTS OF CUSHING DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVE: We conducted a systematic review and meta-analysis to synthesize the evidence about predictors that may affect biochemical remission and recurrence after transsphenoidal surgery (TSS), radiosurgery (RS), and radiotherapy (RT) in Cushing disease. METHODS: We searched multiple databases through December 2014 including original controlled and uncontrolled studies that enrolled patients with Cushing disease who received TSS (first-line), RS, or RT. We extracted data independently, in duplicates. Outcomes of interest were biochemical remission and recurrence. A meta-analysis was conducted using the random-effects model to estimate event rates with 95% confidence intervals (CIs). RESULTS: First-line TSS was associated with high remission (76% [95% CI, 72 to 79%]) and low recurrence rates (10% [95% CI, 6 to 16%]). Remission after TSS was higher in patients with microadenomas or positive-adrenocorticotropic hormone tumor histology. RT was associated with a high remission rate (RS, 68% [95% CI, 61 to 77%]; RT, 66% [95% CI, 58 to 75%]) but also with a high recurrence rate (RS, 32% [95% CI, 16 to 60%]; RT, 26% [95% CI, 14 to 48%]). Remission after RS was higher at short-term follow-up (≤2 years) and with high-dose radiation, while recurrence was higher in women and with lower-dose radiation. Remission was after RT in adults who received TSS prior to RT, and with lower radiation doses. There was heterogeneity (nonstandardization) in the criteria and cutoff points used to define biochemical remission and recurrence. CONCLUSION: First-line TSS is associated with high remission and low recurrence, while RS and RT are associated with reasonable remission rates but important recurrence rates. The current evidence warrants low confidence due to the noncomparative nature of the studies, high heterogeneity, and imprecision.

Quality Improvement Education for Health Professionals: A Systematic Review.

Effective quality improvement (QI) education should improve patient care, but many curriculum studies do not include clinical measures. The research team evaluated the prevalence of QI curricula with clinical measures and their association with several curricular features. MEDLINE, Embase, CINAHL, and ERIC were searched through December 31, 2013. Study selection and data extraction were completed by pairs of reviewers. Of 99 included studies, 11% were randomized, and 53% evaluated clinically relevant measures; 85% were from the United States. The team found that 49% targeted 2 or more health professions, 80% required a QI project, and 65% included coaching. Studies involving interprofessional learners (odds ratio [OR] = 6.55; 95% confidence interval [CI] = 2.71-15.82), QI projects (OR = 13.60; 95% CI = 2.92-63.29), or coaching (OR = 4.38; 95% CI = 1.79-10.74) were more likely to report clinical measures. A little more than half of the published QI curricula studies included clinical measures; they were more likely to include interprofessional learners, QI projects, and coaching.

Predictors of teriparatide treatment failure in patients with low bone mass.

INTRODUCTION: While teriparatide is the only skeletal anabolic agent approved in the United States, treatment failure is a major concern which complicates its clinical utility. We sought to identify factors that predict response failure in patients with low bone mass. METHOD: We performed a retrospective study of adults with osteopenia or osteoporosis (T-scores < - 1.0 and - 2.5 SD below normal, respectively, at the total hip or lumbar spine) treated with teriparatide at the Mayo Clinic (Rochester, Minnesota) between November 2002-December 2012. Trained study investigators blinded to patient outcomes collected electronic medical record data. Potential response failure predictors were identified using univariate analysis. Multivariable logistic regression modeling was used to identify independent predictors of treatment failure based on either osteoporotic fragility fracture or BMD response. RESULTS: During the 10-year period, 494 patients received teriparatide treatment and met eligibility criteria. Thirty-five patients had osteoporotic fractures, while 172 did not achieve a ≥ 3% BMD increase. Among predictors as defined by BMD change, both prior bisphosphonate treatment [odds ratio (95% confidence interval), 1.50 (1.01-2.24)] and vitamin D therapy [1.50 (1.01-2.22)] were significantly (P < 0.05) associated with teriparatide treatment failure. By contrast, no predictors were associated with treatment failure when fracture was the endpoint. CONCLUSION: These data suggest that prior bisphosphonate or vitamin D exposure may predict response failure to teriparatide therapy. Although these findings may, in part, reflect increased severity or longer duration of disease, this knowledge should help guide clinicians and patients when therapy choices are made.

Acting on black box warnings requires a GRADE evidence table and an implementation guide: the case of teriparatide.

OBJECTIVES: To assess how well do the black box warnings present and communicate evidence in a way that is consistent with evidence-based patient-centered practice, through evaluating the boxed warning on teriparatide-induced osteosarcoma. STUDY DESIGN AND SETTING: We critically appraised teriparatide black box warning for osteosarcoma by reviewing human and animal studies that were used as basis for the warning. We also evaluated the quality of the evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. RESULTS: We found that this warning was based on very low-quality evidence that was derived primarily from animal studies. The quality of evidence was rated down because of high risk of bias in addition to inconsistency, indirectness, and imprecision of the estimates. The warning does not provide sufficient guidance for practice like an implementation tool or an evidence profile to clarify the limitations of the evidence. CONCLUSION: Black box warning for teriparatide-associated osteosarcoma does not explicitly present the quality of evidence, and therefore, it could be of limited use in evidence-based practice. We propose that black box warnings should include an evidence profile and an implementation guide to be more useful in evidence-based patient-centered practice.

A systematic review for the screening for peripheral arterial disease in asymptomatic patients.

BACKGROUND: Peripheral arterial disease (PAD) is common and associated with significant morbidity and mortality. PAD can be detected through a noninvasive measurement of the ankle-brachial index (ABI). METHODS: We conducted a systematic review of several electronic bibliographic databases for studies that evaluated ABI as a screening test for PAD in asymptomatic individuals. We conducted random-effects meta-analysis, reporting pooled hazard ratios (HRs) when appropriate. RESULTS: We included 40 individual studies, 2 systematic reviews, and 1 individual-patient data meta-analysis. We found no studies comparing ABI screening with no screening in terms of patient-important outcomes (mortality, amputations). The yield of PAD screening averaged 17% (range, 1%-42%) and was 1% to 4% in lower risk populations. Patients with PAD had higher adjusted risk of all-cause mortality (HR, 2.99; 95% confidence interval, 2.16-4.12) and of cardiovascular mortality (HR, 2.35; 95% confidence interval, 1.91-2.89). Data on benefits, harms, and cost-effectiveness of screening were limited; however, ABI screening was associated with additional prognostic information and risk stratification for heart disease. The overall quality of evidence supporting screening was low. CONCLUSIONS: The current available evidence demonstrates that PAD is common in patients with multiple cardiovascular risk factors and is associated with significant morbidity and mortality, but it does not support the benefit of routine ABI screening.

A systematic review of treatment of intermittent claudication in the lower extremities.

BACKGROUND: Peripheral arterial disease is common and is associated with significant morbidity and mortality. METHODS: We conducted a systematic review to identify randomized trials and systematic reviews of patients with intermittent claudication to evaluate surgery, endovascular therapy, and exercise therapy. Outcomes of interest were death, amputation, walking distance, quality of life, measures of blood flow, and cost. RESULTS: We included eight systematic reviews and 12 trials enrolling 1548 patients. Data on mortality and amputation and on cost-effectiveness were sparse. Compared with medical management, each of the three treatments (surgery, endovascular therapy, and exercise therapy) was associated with improved walking distance, claudication symptoms, and quality of life (high-quality evidence). Evidence supporting superiority of one of the three approaches was limited. However, blood flow parameters improved faster and better with both forms of revascularization compared with exercise or medical management (low- to moderate-quality evidence). Compared with endovascular therapy, open surgery may be associated with longer length of hospital stay and higher complication rate but resulted in more durable patency (moderate-quality evidence). CONCLUSIONS: In patients with claudication, open surgery, endovascular therapy, and exercise therapy were superior to medical management in terms of walking distance and claudication. Choice of therapy should rely on patients' values and preferences, clinical context, and availability of operative expertise.

The incremental benefit of functional imaging in pheochromocytoma/paraganglioma: a systematic review.

Computed tomography (CT) and magnetic resonance imaging (MRI) are the major imaging modalities used for the localization of catecholamine-producing tumors (pheochromocytoma and paraganglioma). Functional imaging (FI) offers an alternative approach to localize, evaluate, and stage these tumors. Our objective was to describe the additive benefit of FI studies for patients with pheochromocytoma and paraganglioma (PPG) who have undergone MRI or CT scan evaluation. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from database inception through June 2012 for studies that included patients with biochemically proven PPGs who underwent CT or MRI and additional FI for the localization of PPGs. We included 32 studies enrolling a total of 1,264 patients with a mean age of 43-years old. The studies were uncontrolled and evaluated six FI modalities. FI tests provided small additive value to CT/MRI, aiding in the localization of only 24/1,445 primary cases (1.4 %) and 28/805 metastatic cases (3.5 %). In metastatic cases, 6-[F-18]fluoro-L-dihydroxyphenylalanine (DOPA) and fluorodopamine-PET (FDA) were the FI tests most successful at identifying disease missed by CT/MRI, providing additional benefit in 6/60 (10 %) and 5/78 (6.4 %) cases, respectively. No clinically significant findings were observed in any of the predefined subgroups. No study evaluated the impact of FI on the completeness of surgical resection or other patient-important outcomes. Observational evidence suggests that FI tests have a limited additional role in patients with PPGs who have undergone CT/MRI evaluation. However, the role of FI tests in specific subgroups of patients with atypical presentations (metastatic, extra-adrenal) as well as the use of hybrid FI tests should be explored. Further research should also evaluate the impact of FI tests on patient-important outcomes.

Clinical review: Drugs commonly associated with weight change: a systematic review and meta-analysis.

CONTEXT: Various drugs affect body weight as a side effect. OBJECTIVE: We conducted this systematic review and meta-analysis to summarize the evidence about commonly prescribed drugs and their association with weight change. DATA SOURCES: MEDLINE, DARE, and the Cochrane Database of Systematic Reviews were searched to identify published systematic reviews as a source for trials. STUDY SELECTION: We included randomized trials that compared an a priori selected list of drugs to placebo and measured weight change. DATA EXTRACTION: We extracted data in duplicate and assessed the methodological quality using the Cochrane risk of bias tool. RESULTS: We included 257 randomized trials (54 different drugs; 84 696 patients enrolled). Weight gain was associated with the use of amitriptyline (1.8 kg), mirtazapine (1.5 kg), olanzapine (2.4 kg), quetiapine (1.1 kg), risperidone (0.8 kg), gabapentin (2.2 kg), tolbutamide (2.8 kg), pioglitazone (2.6 kg), glimepiride (2.1 kg), gliclazide (1.8 kg), glyburide (2.6 kg), glipizide (2.2 kg), sitagliptin (0.55 kg), and nateglinide (0.3 kg). Weight loss was associated with the use of metformin (1.1 kg), acarbose (0.4 kg), miglitol (0.7 kg), pramlintide (2.3 kg), liraglutide (1.7 kg), exenatide (1.2 kg), zonisamide (7.7 kg), topiramate (3.8 kg), bupropion (1.3 kg), and fluoxetine (1.3 kg). For many other remaining drugs (including antihypertensives and antihistamines), the weight change was either statistically nonsignificant or supported by very low-quality evidence. CONCLUSIONS: Several drugs are associated with weight change of varying magnitude. Data are provided to guide the choice of drug when several options exist and institute preemptive weight loss strategies when obesogenic drugs are prescribed.

Patient and service user engagement in research: a systematic review and synthesized framework.

BACKGROUND: There is growing attention towards increasing patient and service user engagement (PSUE) in biomedical and health services research. Existing variations in language and design inhibit reporting and indexing, which are crucial to comparative effectiveness in determining best practices. OBJECTIVE: This paper utilizes a systematic review and environmental scan to derive an evidence-based framework for PSUE. DESIGN: A metanarrative systematic review and environmental scan/manual search using scientific databases and other search engines, along with feedback from a patient advisory group (PAG). ELIGIBLE SOURCES: English-language studies, commentaries, grey literature and other sources (including systematic and non-systematic reviews) pertaining to patient and public involvement in biomedical and health services research. DATA EXTRACTED: Study description (e.g. participant demographics, research setting) and design, if applicable; frameworks, conceptualizations or planning schemes for PSUE-related endeavours; and methods for PSUE initiation and gathering patients'/service users' input or contributions. RESULTS: Overall, 202 sources were included and met eligibility criteria; 41 of these presented some framework or conceptualization of PSUE. Sources were synthesized into a two-part framework for PSUE: (i) integral PSUE components include patient and service user initiation, reciprocal relationships, colearning and re-assessment and feedback, (ii) sources describe PSUE at several research stages, within three larger phases: preparatory, execution and translational. DISCUSSION AND CONCLUSIONS: Efforts at developing a solid evidence base on PSUE are limited by the non-standard and non-empirical nature of much of the literature. Our proposed two-part framework provides a standard structure and language for reporting and indexing to support comparative effectiveness and optimize PSUE.