Readmissions after Hospitalization for Heart Failure,Acute Myocardial Infarction,or Pneumonia among Young and Middle-Aged Adults: A Retrospective Observational Cohort Study

Background

Patients aged ≥65 years are vulnerable to readmissions due to a transient period of generalized risk after hospitalization. However, whether young and middle-aged adults share a similar risk pattern is uncertain. We compared the rate, timing, and readmission diagnoses following hospitalization for heart failure (HF), acute myocardial infarction (AMI), and pneumonia among patients aged 18–64 years with patients aged ≥65 years.

Methods and Findings

We used an all-payer administrative dataset from California consisting of all hospitalizations for HF (n = 206,141), AMI (n = 107,256), and pneumonia (n = 199,620) from 2007–2009. The primary outcomes were unplanned 30-day readmission rate, timing of readmission, and readmission diagnoses. Our findings show that the readmission rate among patients aged 18–64 years exceeded the readmission rate in patients aged ≥65 years in the HF cohort (23.4% vs. 22.0%, p<0.001), but was lower in the AMI (11.2% vs. 17.5%, p<0.001) and pneumonia (14.4% vs. 17.3%, p<0.001) cohorts. When adjusted for sex, race, comorbidities, and payer status, the 30-day readmission risk in patients aged 18–64 years was similar to patients ≥65 years in the HF (HR 0.99; 95%CI 0.97–1.02) and pneumonia (HR 0.97; 95%CI 0.94–1.01) cohorts and was marginally lower in the AMI cohort (HR 0.92; 95%CI 0.87–0.96). For all cohorts, the timing of readmission was similar; readmission risks were highest between days 2 and 5 and declined thereafter across all age groups. Diagnoses other than the index admission diagnosis accounted for a substantial proportion of readmissions among age groups <65 years; a non-cardiac diagnosis represented 39–44% of readmissions in the HF cohort and 37–45% of readmissions in the AMI cohort, while a non-pulmonary diagnosis represented 61–64% of patients in the pneumonia cohort.

Conclusion

When adjusted for differences in patient characteristics, young and middle-aged adults have 30-day readmission rates that are similar to elderly patients for HF, AMI, and pneumonia. A generalized risk after hospitalization is present regardless of age. Please see later in the article for the Editors'' Summary     

Intravenous N-Acetylcysteine for Prevention of Contrast-Induced Nephropathy: A Meta-Analysis of Randomized,Controlled Trials

Background

Contrast-induced nephropathy (CIN) is one of the common causes of acute renal insufficiency after contrast procedures. Whether intravenous N-acetylcysteine (NAC) is beneficial for the prevention of contrast-induced nephropathy is uncertain. In this meta-analysis of randomized controlled trials, we aimed to assess the efficacy of intravenous NAC for preventing CIN after administration of intravenous contrast media.

Study Design

Relevant studies published up to September 2012 that investigated the efficacy of intravenous N-acetylcysteine for preventing CIN were collected from MEDLINE, OVID, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and the conference proceedings from major cardiology and nephrology meetings. The primary outcome was CIN. Secondary outcomes included renal failure requiring dialysis, mortality, and length of hospitalization. Data were combined using random-effects models with the performance of standard tests to assess for heterogeneity and publication bias. Meta-regression analyses were also performed.

Results

Ten trials involving 1916 patients met our inclusion criteria. Trials varied in patient demographic characteristics, inclusion criteria, dosing regimens, and trial quality. The summary risk ratio for contrast-induced nephropathy was 0.68 (95% CI, 0.46 to 1.02), a nonsignificant trend towards benefit in patients treated with intravenous NAC. There was evidence of significant heterogeneity in NAC effect across studies (Q = 17.42, P = 0.04; I² = 48%). Meta-regression revealed no significant relation between the relative risk of CIN and identified differences in participant or study characteristics.

Conclusion

This meta-analysis showed that research on intravenous N-acetylcysteine and the incidence of CIN is too inconsistent at present to warrant a conclusion on efficacy. A large, well designed trial that incorporates the evaluation of clinically relevant outcomes in participants with different underlying risks of CIN is required to more adequately assess the role for intravenous NAC in CIN prevention.     

Clinical and Financial Outcomes Due to Methicillin Resistant Staphylococcus aureus Surgical Site Infection: A Multi-Center Matched Outcomes Study

Background

The clinical and financial outcomes of SSIs directly attributable to MRSA and methicillin-resistance are largely uncharacterized. Previously published data have provided conflicting conclusions.

Methodology

We conducted a multi-center matched outcomes study of 659 surgical patients. Patients with SSI due to MRSA were compared with two groups: matched uninfected control patients and patients with SSI due to MSSA. Four outcomes were analyzed for the 90-day period following diagnosis of the SSI: mortality, readmission, duration of hospitalization, and hospital charges. Attributable outcomes were determined by logistic and linear regression.

Principal Findings

In total, 150 patients with SSI due to MRSA were compared to 231 uninfected controls and 128 patients with SSI due to MSSA. SSI due to MRSA was independently predictive of readmission within 90 days (OR = 35.0, 95% CI 17.3–70.7), death within 90 days (OR = 7.27, 95% CI 2.83–18.7), and led to 23 days (95% CI 19.7–26.3) of additional hospitalization and $61,681 (95% 23,352–100,011) of additional charges compared with uninfected controls. Methicillin-resistance was not independently associated with increased mortality (OR = 1.72, 95% CI 0.70–4.20) nor likelihood of readmission (OR = 0.43, 95% CI 0.21–0.89) but was associated with 5.5 days (95% CI 1.97–9.11) of additional hospitalization and $24,113 (95% 4,521–43,704) of additional charges.

Conclusions/Significance

The attributable impact of S. aureus and methicillin-resistance on outcomes of surgical patients is substantial. Preventing a single case of SSI due to MRSA can save hospitals as much as $60,000.     

NSFC Health Research Funding and Burden of Disease in China

Background

Allocation of health research funds among diseases has never been evaluated in China. This study aimed to examine the relationship between disease-specific funding levels of National Nature Science Foundation of China (NSFC), the main governmental resource for health research in China, and burden of disease.

Methods

Funding magnitudes for 53 diseases or conditions were obtained from the website of NSFC. Measures of disease burden, mortality, years of life lost (YLLs) and disability-adjusted life years (DALYs), were derived from the Global Burden of Disease Study 2010. The relationship between NSFC funding and disease burden was analyzed with univariate linear regression. For each measure associated with funding, regression-derived estimates were used to calculate the expected funds for each disease. The actual and expected funds were then compared. We also evaluated the impacts of changes of disease burden metrics since 1990, and differences from the world averages on NSFC funding.

Results

NSFC health research funding was associated with disease burden measured in mortality (R = 0.33, P = 0.02), YLLs (R = 0.39, P = 0.004), and DALYs (R = 0.40, P = 0.003). But none of the changes of mortality (R = 0.22, P = 0.12), YLLs (R = −0.04, P = 0.79) and DALYs (R = −0.003, P = 0.98) since 1990 was associated with the funding magnitudes. None of the differences of mortality (R = −0.11, P = 0.45), YLLs (R = −0.11, P = 0.43) and DALYs (R = −0.12, P = 0.38) from that of the concurrent world averages were associated with the funding magnitudes. Measured by DALY, stroke and COPD received the least funding compared to expected; while leukemia and diabetes received the most funding compared to expected.

Conclusion

Although NSFC funding were roughly associated with disease burden as measured in mortality, YLLs and DALYs. Some major diseases such as stroke were underfunded; while others such as leukaemia were overfunded. Change of disease burden during the last 20 years and country-specialized disease burden were not reflected in current allocation of NSFC funds.     

The evidence base for interventions delivered to children in primary care: an overview of cochrane systematic reviews

Background

As a first step in developing a framework to evaluate and improve the quality of care of children in primary care there is a need to identify the evidence base underpinning interventions relevant to child health. Our objective was to identify all Cochrane systematic reviews relevant to the management of childhood conditions in primary care and to assess the extent to which Cochrane reviews reflect the burden of childhood illness presenting in primary care.

Methodology/Principal Findings

We used the Cochrane Child Health Field register of child-relevant systematic reviews to complete an overview of Cochrane reviews related to the management of children in primary care. We compared the proportion of systematic reviews with the proportion of consultations in Australia, US, Dutch and UK general practice in children. We identified 396 relevant systematic reviews; 358 included primary studies on children while 251 undertook a meta-analysis. Most reviews (n = 218, 55%) focused on chronic conditions and over half (n = 216, 57%) evaluated drug interventions. Since 2000, the percentage of pediatric primary care relevant reviews only increased by 2% (7% to 9%) compared to 18% (10% to 28%) in all child relevant reviews. Almost a quarter of reviews (n = 78, 23%) were published on asthma treatments which only account for 3–5% of consultations. Conversely, 15–23% of consultations are due to skin conditions yet they represent only 7% (n = 23) of reviews.

Conclusions/Significance

Although Cochrane systematic reviews focus on clinical trials and do not provide a comprehensive picture of the evidence base underpinning the management of children in primary care, the mismatch between the focus of the published research and the focus of clinical activity is striking. Clinical trials are an important component of the evidence base and the lack of trial evidence to demonstrate intervention effectiveness in substantial areas of primary care for children should be addressed.     

Is Early Oral Feeding after Gastric Cancer Surgery Feasible? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Aim

To assess the feasibility and safety of early oral feeding (EOF) after gastrectomy for gastric cancer through a systematic review and meta-analysis based on randomized controlled trials.

Methods

A literature search in PubMed, Embase, Web of Science and Cochrane library databases was performed for eligible studies published between January 1995 and March 2014. Systematic review was carried out to identify randomized controlled trials comparing EOF and traditional postoperative oral feeding after gastric cancer surgery. Meta-analyses were performed by either a fixed effects model or a random effects model according to the heterogeneity using RevMan 5.2 software.

Results

Six studies remained for final analysis. Included studies were published between 2005 and 2013 reporting on a total of 454 patients. No significant differences were observed for postoperative complication (RR = 0.95; 95%CI, 0.70 to 1.29; P = 0.75), the tolerability of oral feeding (RR = 0.98; 95%CI, 0.91 to 1.06; P = 0.61), readmission rate (RR = 1; 95%CI, 0.30 to 3.31; P = 1.00) and incidence of anastomotic leakage (RR = 0.31; 95%CI, 0.01 to 7.30; P = 0.47) between two groups. EOF after gastrectomy for gastric cancer was associated with significant shorter duration of the hospital stay (WMD = −2.36; 95%CI, −3.37 to −1.34; P<0.0001) and time to first flatus (WMD = −19.94; 95%CI, −32.03 to −7.84; P = 0.001). There were no significant differences in postoperative complication, tolerability of oral feeding, readmission rates, duration of hospital stay and time to first flatus among subgroups stratified by the time to start EOF or by partial and total gastrectomy or by laparoscopic and open surgery.

Conclusions

The result of this meta-analysis showed that EOF after gastric cancer surgery seems feasible and safe, even started at the day of surgery irrespective of the extent of the gastric resection and the type of surgery. However, more prospective, well-designed multicenter RCTs with more clinical outcomes are needed for further validation.     

Development,Validation and Deployment of a Real Time 30 Day Hospital Readmission Risk Assessment Tool in the Maine Healthcare Information Exchange

ObjectivesIdentifying patients at risk of a 30-day readmission can help providers design interventions, and provide targeted care to improve clinical effectiveness. This study developed a risk model to predict a 30-day inpatient hospital readmission for patients in Maine, across all payers, all diseases and all demographic groups.MethodsOur objective was to develop a model to determine the risk for inpatient hospital readmission within 30 days post discharge. All patients within the Maine Health Information Exchange (HIE) system were included. The model was retrospectively developed on inpatient encounters between January 1, 2012 to December 31, 2012 from 24 randomly chosen hospitals, and then prospectively validated on inpatient encounters from January 1, 2013 to December 31, 2013 using all HIE patients.ResultsA risk assessment tool partitioned the entire HIE population into subgroups that corresponded to probability of hospital readmission as determined by a corresponding positive predictive value (PPV). An overall model c-statistic of 0.72 was achieved. The total 30-day readmission rates in low (score of 0–30), intermediate (score of 30–70) and high (score of 70–100) risk groupings were 8.67%, 24.10% and 74.10%, respectively. A time to event analysis revealed the higher risk groups readmitted to a hospital earlier than the lower risk groups. Six high-risk patient subgroup patterns were revealed through unsupervised clustering. Our model was successfully integrated into the statewide HIE to identify patient readmission risk upon admission and daily during hospitalization or for 30 days subsequently, providing daily risk score updates.ConclusionsThe risk model was validated as an effective tool for predicting 30-day readmissions for patients across all payer, disease and demographic groups within the Maine HIE. Exposing the key clinical, demographic and utilization profiles driving each patient’s risk of readmission score may be useful to providers in developing individualized post discharge care plans.     

A Meta-Analysis of P2X7 Gene-762T/C Polymorphism and Pulmonary Tuberculosis Susceptibility

AimWe performed a comprehensive meta-analysis to determine the association between P2X7 -762T/C polymorphism and pulmonary tuberculosis susceptibility.MethodologyBased on comprehensive searches of the PubMed, SCI, Elsevier, China National Knowledge Infrastructure (CNKI) and Wanfang Database, we identified eligible studies about the association between P2X7 -762T/C polymorphism and pulmonary tuberculosis risk. Pooled odds ratio (ORs) and 95% confidence intervals (95%CIs) were calculated in random-effects model.ResultsA total of 2207 tuberculosis cases and 2220 controls in 8 case-control studies were included in this meta-analysis. Allele model (C vs. T: p = 0.15; OR = 0.83, 95% CI = 0.65–1.07), homozygous model (CC vs. TT: p = 0.23; OR = 0.73, 95% CI = 0.44 to 1.22), and heterozygous model (CT vs. TT: p = 0.57; OR = 0.92, 95% CI = 0.68 to 1.24) did not show increased risk of developing pulmonary tuberculosis. Similarly, dominant model (CC+CT vs. TT: p = 0.32; OR = 0.84, 95% CI = 0.59 to 1.19) and recessive model (CC vs. CT+TT: p = 0.08; OR = 0.77, 95% CI = 0.57 to 1.04) failed to show increased risk of developing pulmonary tuberculosis. Subgroup analysis by ethnicity did not detect any significant association between P2X7–762T/C polymorphism and pulmonary tuberculosis susceptibility.ConclusionsP2X7 -762T/C gene polymorphism is not associated with pulmonary tuberculosis susceptibility.     

Correlations of MTHFR 677C>T Polymorphism with Cardiovascular Disease in Patients with End-Stage Renal Disease: A Meta-Analysis

ObjectiveThis meta-analysis was conducted to evaluate the correlations of a common polymorphism (677C>T) in the methylenetetrahydrofolate reductase (MTHFR) gene with risk of cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD).MethodThe following electronic databases were searched without language restrictions: Web of Science (1945∼2013), the Cochrane Library Database (Issue 12, 2013), MEDLINE (1966∼2013), EMBASE (1980∼2013), CINAHL (1982∼2013) and the Chinese Biomedical Database (CBM) (1982∼2013). Meta-analysis was performed using STATA statistical software. Odds ratios (ORs) with their 95% confidence intervals (95%CIs) were calculated.ResultsEight cohort studies met all inclusion criteria and were included in this meta-analysis. A total of 2,292 ESRD patients with CVD were involved in this meta-analysis. Our meta-analysis results revealed that the MTHFR 677C>T polymorphism might increase the risk of CVD in ESRD patients (TT vs. CC: OR = 2.75, 95%CI = 1.35∼5.59, P = 0.005; CT+TT vs. CC: OR = 1.39, 95%CI = 1.09∼1.78, P = 0.008; TT vs. CC+CT: OR = 2.52, 95%CI = 1.25∼5.09, P = 0.010; respectively). Further subgroup analysis by ethnicity suggested that the MTHFR 677C>T polymorphism was associated with an elevated risk for CVD in ESRD patients among Asians (TT vs. CC: OR = 3.38, 95%CI = 1.11∼10.28, P = 0.032; CT+TT vs. CC: OR = 1.44, 95%CI = 1.05∼1.97, P = 0.022; TT vs. CC+CT: OR = 3.15, 95%CI = 1.02∼9.72, P = 0.046; respectively), but not among Africans or Caucasians (all P>0.05).ConclusionOur findings indicate that the MTHFR 677C>T polymorphism may be associated with an elevated risk for CVD in ESRD patients, especially among Asians.     

Disparities in Oral Cancer Survival among Mentally Ill Patients

Background

Many studies have reported excess cancer mortality in patients with mental illness. However, scant studies evaluated the differences in cancer treatment and its impact on survival rates among mentally ill patients. Oral cancer is one of the ten most common cancers in the world. We investigated differences in treatment type and survival rates between oral cancer patients with mental illness and without mental illness.

Methods

Using the National Health Insurance (NHI) database, we compared the type of treatment and survival rates in 16687 oral cancer patients from 2002 to 2006. The utilization rate of surgery for oral cancer was compared between patients with mental illness and without mental illness using logistic regression. The Cox proportional hazards model was used for survival analysis.

Results

Oral cancer patients with mental disorder conferred a grave prognosis, compared with patients without mental illness (hazard ratios [HR] = 1.58; 95% confidence interval [CI] = 1.30–1.93; P<0.001). After adjusting for patients’ characteristics and hospital characteristics, patients with mental illness were less likely to receive surgery with or without adjuvant therapy (odds ratio [OR] = 0.47; 95% CI = 0.34–0.65; P<0.001). In multivariate analysis, oral cancer patients with mental illness carried a 1.58-times risk of death (95% CI = 1.30–1.93; P<0.001).

Conclusions

Oral cancer patients with mental illness were less likely to undergo surgery with or without adjuvant therapy than those without mental illness. Patients with mental illness have a poor prognosis compared to those without mental illness. To reduce disparities in physical health, public health strategies and welfare policies must continue to focus on this vulnerable group.     

Phylogenetic Analysis Reveals Common Antimicrobial Resistant Campylobacter coli Population in Antimicrobial-Free (ABF) and Commercial Swine Systems

The objective of this study was to compare the population biology of antimicrobial resistant (AR) Campylobacter coli isolated from swine reared in the conventional and antimicrobial-free (ABF) swine production systems at farm, slaughter and environment. A total of 200 C. coli isolates selected from fecal, environmental, and carcass samples of ABF (n = 100) and conventional (n = 100) swine production systems were typed by multilocus sequence typing (MLST). Sequence data from seven housekeeping genes was analyzed for the identification of allelic profiles, sequence types (STs) and clonal complex determination. Phylogenetic trees were generated to establish the relationships between the genotyped isolates. A total of 51 STs were detected including two novel alleles (glnA 424 and glyA 464) and 14 novel STs reported for the first time. The majority of the C. coli isolates belonged to ST-854 (ABF: 31, conventional: 17), and were grouped in clonal complex ST-828 (ABF: 68%, conventional: 66%). The mean genetic diversity (H) for the ABF (0.3963+/−0.0806) and conventional (0.4655+/−0.0714) systems were similar. The index of association () for the ABF ( = 0.1513) and conventional ( = 0.0991) C. coli populations were close to linkage equilibrium, indicative of a freely recombining population. Identical STs were detected between the pigs and their environment both at farm and slaughter. A minimum spanning tree revealed the close clustering of C. coli STs that originated from swine and carcass with those from the environment. In conclusion, our study reveals a genotypic diverse C. coli population that shares a common ancestry in the conventional and ABF swine production systems. This could potentially explain the high prevalence of antimicrobial resistant C. coli in the ABF system in the absence of antimicrobial selection pressure.     

The Role of Decision Support System (DSS) in Prevention of Cardiovascular Disease: A Systematic Review and Meta-Analysis

Background

The potential role of DSS in CVD prevention remains unclear as only a few studies report on patient outcomes for cardiovascular disease.

Methods and Results

A systematic review and meta-analysis of randomised controlled trials and observational studies was done using Medline, Embase, Cochrane Library, PubMed, Amed, CINAHL, Web of Science, Scopus databases; reference lists of relevant studies to 30 July 2011; and email contact with experts. The primary outcome was prevention of cardiovascular disorders (myocardial infarction, stroke, coronary heart disease, peripheral vascular disorders and heart failure) and management of hypertension owing to decision support systems, clinical decision supports systems, computerized decision support systems, clinical decision making tools and medical decision making (interventions). From 4116 references ten studies met our inclusion criteria (including 16,312 participants). Five papers reported outcomes on blood pressure management, one paper on heart failure, two papers each on stroke, and coronary heart disease. The pooled estimate for CDSS versus control group differences in SBP (mm of Hg) was - 0.99 (95% CI −3.02 to 1.04 mm of Hg; I² = 0; p = 0.851).

Conclusions

DSS show an insignificant benefit in the management and control of hypertension (insignificant reduction of SBP). The paucity of well-designed studies on patient related outcomes is a major hindrance that restricts interpretation for evaluating the role of DSS in secondary prevention. Future studies on DSS should (1) evaluate both physician performance and patient outcome measures (2) integrate into the routine clinical workflow with a provision for decision support at the point of care.     

Hospital Readmissions of Patients with Heart Failure: The Impact of Hospital and Primary Care Organizational Factors in Northern Italy

BackgroundPrimary health care is essential for an appropriate management of heart failure (HF), a disease which is a major clinical and public health issue and a leading cause of hospitalization. The aim of this study was to evaluate the impact of different organizational factors on readmissions of patients with HF.MethodsThe study population included elderly resident in the Local Health Authority of Bologna (Northern Italy) and discharged with a diagnosis of HF from January to December 2010. Unplanned hospital readmissions were measured in four timeframes: 30 (short-term), 90 (medium-term), 180 (mid-long-term), and 365 days (long-term). Using multivariable multilevel Poisson regression analyses, we investigated the association between readmissions and organizational factors (discharge from a cardiology department, general practitioners’ monodisciplinary organizational arrangement, and implementation of a specific HF care pathway).ResultsThe 1873 study patients had a median age of 83 years (interquartile range 77–87) and 55.5% were females; 52.0% were readmitted to the hospital for any reason after a year, while 20.1% were readmitted for HF. The presence of a HF care pathway was the only factor significantly associated with a lower risk of readmission for HF in the short-, medium-, mid-long- and long-term period (short-term: IRR [incidence rate ratio]=0.57, 95%CI [confidence interval]=0.35–0.92; medium-term: IRR=0.70, 95%CI=0.51–0.96; mid-long-term: IRR=0.79, 95%CI=0.64–0.98; long-term: IRR=0.82, 95%CI=0.67–0.99), and with a lower risk of all-cause readmission in the short-term period (IRR=0.73, 95%CI=0.57–0.94).ConclusionOur study shows that the HF care specific pathway implemented at the primary care level was associated with lower readmission rate for HF in each timeframe, and also with lower readmission rate for all causes in the short-term period. Our results suggest that the engagement of primary care professionals starting from the early post-discharge period may be relevant in the management of patients with HF.     

Natriuretic Peptide-Guided Therapy in Chronic Heart Failure: A Meta-Analysis of 2,686 Patients in 12 Randomized Trials

Background

The role of cardiac natriuretic peptides in the management of patients with chronic heart failure (HF) remains uncertain. The purpose of this study was to evaluate whether natriuretic peptide-guided therapy, compared to clinically-guided therapy, improves mortality and hospitalization rate in patients with chronic HF.

Methodology/Principal Findings

MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases were searched for articles reporting natriuretic peptide-guided therapy in HF until August 2012. All randomized trials reporting clinical end-points (all-cause mortality and/or HF-related hospitalization and/or all-cause hospitalization) were included. Meta-analysis was performed to assess the influence of treatment on outcomes. Sensitivity analysis was performed to test the influence of potential effect modifiers and of each trial included in meta-analysis on results. Twelve trials enrolling 2,686 participants were included. Natriuretic peptide-guided therapy (either B-type natriuretic peptide [BNP]- or N-terminal pro-B-type natriuretic peptide [NT-proBNP]-guided therapy) significantly reduced all-cause mortality (Odds Ratio [OR]:0.738; 95% Confidence Interval [CI]:0.596 to 0.913; p = 0.005) and HF-related hospitalization (OR:0.554; CI:0.399 to 0.769; p = 0.000), but not all-cause hospitalization (OR:0.803; CI:0.629 to 1.024; p = 0.077). When separately assessed, NT-proBNP-guided therapy significantly reduced all-cause mortality (OR:0.717; CI:0.563 to 0.914; p = 0.007) and HF-related hospitalization (OR:0.531; CI:0.347 to 0.811; p = 0.003), but not all-cause hospitalization (OR:0.779; CI:0.414 to 1.465; p = 0.438), whereas BNP-guided therapy did not significantly reduce all-cause mortality (OR:0.814; CI:0.518 to 1.279; p = 0.371), HF-related hospitalization (OR:0.599; CI:0.303 to 1.187; p = 0.142) or all-cause hospitalization (OR:0.726; CI:0.609 to 0.964; p = 0.077).

Conclusions/Significance

Use of cardiac peptides to guide pharmacologic therapy significantly reduces mortality and HF related hospitalization in patients with chronic HF. In particular, NT-proBNP-guided therapy reduced all-cause mortality and HF-related hospitalization but not all-cause hospitalization, whereas BNP-guided therapy did not significantly reduce both mortality and morbidity.     

Poor Reliability between Cochrane Reviewers and Blinded External Reviewers When Applying the Cochrane Risk of Bias Tool in Physical Therapy Trials

Objectives

To test the inter-rater reliability of the RoB tool applied to Physical Therapy (PT) trials by comparing ratings from Cochrane review authors with those of blinded external reviewers.

Methods

Randomized controlled trials (RCTs) in PT were identified by searching the Cochrane Database of Systematic Reviews for meta-analysis of PT interventions. RoB assessments were conducted independently by 2 reviewers blinded to the RoB ratings reported in the Cochrane reviews. Data on RoB assessments from Cochrane reviews and other characteristics of reviews and trials were extracted. Consensus assessments between the two reviewers were then compared with the RoB ratings from the Cochrane reviews. Agreement between Cochrane and blinded external reviewers was assessed using weighted kappa (κ).

Results

In total, 109 trials included in 17 Cochrane reviews were assessed. Inter-rater reliability on the overall RoB assessment between Cochrane review authors and blinded external reviewers was poor (κ  =  0.02, 95%CI: −0.06, 0.06]). Inter-rater reliability on individual domains of the RoB tool was poor (median κ  = 0.19), ranging from κ  =  −0.04 (“Other bias”) to κ  =  0.62 (“Sequence generation”). There was also no agreement (κ  =  −0.29, 95%CI: −0.81, 0.35]) in the overall RoB assessment at the meta-analysis level.

Conclusions

Risk of bias assessments of RCTs using the RoB tool are not consistent across different research groups. Poor agreement was not only demonstrated at the trial level but also at the meta-analysis level. Results have implications for decision making since different recommendations can be reached depending on the group analyzing the evidence. Improved guidelines to consistently apply the RoB tool and revisions to the tool for different health areas are needed.     

The Value of Neuraminidase Inhibitors for the Prevention and Treatment of Seasonal Influenza: A Systematic Review of Systematic Reviews

Controversy has arisen regarding the effectiveness of neuraminidase inhibitors (NIs), especially against influenza-related complications. A literature search was performed to critically assess the evidence collected by the available systematic reviews (SRs) regarding the benefits and disadvantages of NIs (oseltamivir, zanamivir) compared to placebos in healthy and at-risk individuals of all ages for prophylaxis and treatment of seasonal influenza. A SR was done using the Cochrane Database of Systematic Reviews, Health Technology Assessment Database, Database of Abstracts of Reviews of Effects, and Medline (January 2006–July 2012). Two reviewers selected SRs based on randomized clinical trials, which were restricted to intention-to-treat results, and they assessed review (AMSTAR) and study quality indicators (GRADE). The SRs included (N = 9) were of high quality. The efficacy of NIs in prophylaxis ranged from 64% (16–85) to 92% (37–99); the absolute risk reduction ranged from 1.2% to 12.1% (GRADE moderate to low). Clinically relevant treatment benefits of NIs were small in healthy adults and children suffering from influenza-like illness (GRADE high to moderate). Oseltamivir reduced antibiotic usage in healthy adults according to one SR, but this was not confirmed by other reviews (GRADE low). Zanamivir showed a preventive effect on antibiotic usage in children (95% (77–99);GRADE moderate) and on the occurrence of bronchitis in at-risk individuals (59% (30–76);GRADE moderate). No evidence was available on the treatment benefits of NIs in elderly and at-risk groups and their effects on hospitalization and mortality. In oseltamivir trials, nausea, vomiting and diarrhea were significant side-effects. For zanamivir trials, no adverse effects have been reported. The combination of diagnostic uncertainty, the risk for virus strain resistance, possible side effects and financial cost outweigh the small benefits of oseltamivir or zanamivir for the prophylaxis and treatment of healthy individuals. No relevant benefits of these NIs on complications in at-risk individuals have been established.     

Chewing Betel Quid and the Risk of Metabolic Disease,Cardiovascular Disease,and All-Cause Mortality: A Meta-Analysis

Background

Betel nut (Areca nut) is the fruit of the Areca catechu tree. Approximately 700 million individuals regularly chew betel nut (or betel quid) worldwide and it is a known risk factor for oral cancer and esophageal cancer. We performed a meta-analysis to assess the influence of chewing betel quid on metabolic diseases, cardiovascular disease, and all-cause mortality.

Methodology/Principal Findings

We searched Medline, Cochrane Library, Web of Science, and Science Direct for pertinent articles (including the references) published between 1951 and 2013. The adjusted relative risk (RR) and 95% confidence interval were calculated using the random effect model. Sex was used as an independent category for comparison.

Results

Of 580 potentially relevant studies, 17 studies from Asia (5 cohort studies and 12 case-control studies) covering 388,134 subjects (range: 94 to 97,244) were selected. Seven studies (N = 121,585) showed significant dose-response relationships between betel quid consumption and the risk of events. According to pooled analysis, the adjusted RR of betel quid chewers vs. non-chewers was 1.47 (P<0.001) for obesity (N = 30,623), 1.51 (P = 0.01) for metabolic syndrome (N = 23,291), 1.47 (P<0.001) for diabetes (N = 51,412), 1.45 (P = 0.06) for hypertension (N = 89,051), 1.2 (P = 0.02) for cardiovascular disease (N = 201,488), and 1.21 (P = 0.02) for all-cause mortality (N = 179,582).

Conclusion/Significance

Betel quid chewing is associated with an increased risk of metabolic disease, cardiovascular disease, and all-cause mortality. Thus, in addition to preventing oral cancer, stopping betel quid use could be a valuable public health measure for metabolic diseases that are showing a rapid increase in South-East Asia and the Western Pacific.     

Financing of U.S. Biomedical Research and New Drug Approvals across Therapeutic Areas

Background

We estimated U.S. biomedical research funding across therapeutic areas, determined the association with disease burden, and evaluated new drug approvals that resulted from this investment.

Methodology/Principal Findings

We calculated funding from 1995 to 2005 and totaled Food and Drug Administration approvals in eight therapeutic areas (cardiovascular, endocrine, gastrointestinal, genitourinary, HIV/AIDS, infectious disease excluding HIV, oncology, and respiratory) primarily using public data. We then calculated correlations between funding, published estimates of disease burden, and drug approvals.Financial support for biomedical research from 1995 to 2005 increased across all therapeutic areas between 43% and 369%. Industry was the principal funder of all areas except HIV/AIDS, infectious disease, and oncology, which were chiefly sponsored by the National Institutes of Health (NIH). Total (ρ = 0.70; P = .03) and industry funding (ρ = 0.69; P = .04) were correlated with projected disease burden in high income countries while NIH support (ρ = 0.80; P = .01) was correlated with projected disease burden globally. From 1995 to 2005 the number of new approvals was flat or declined across therapeutic areas, and over an 8-year lag period, neither total nor industry funding was correlated with future approvals.

Conclusions/Significance

Across therapeutic areas, biomedical research funding increased substantially, appears aligned with disease burden in high income countries, but is not linked to new drug approvals. The translational gap between funding and new therapies is affecting all of medicine, and remedies must include changes beyond additional financial investment.