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Importance: Acute respiratory infections (ARIs) account for most outpatient visits. Discriminating bacterial vs viral etiology is a diagnostic challenge with therapeutic implications., Objective: To investigate whether FebriDx, a rapid, point-of-care immunoassay, can differentiate bacterial- from viral-associated host immune response in ARI through measurement of myxovirus resistance protein A (MxA) and C-reactive protein (CRP) from finger-stick blood., Design, Setting, and Participants: This diagnostic study enrolled adults and children who were symptomatic for ARI and individuals in a control group who were asymptomatic between October 2019 and April 2021. Included participants were a convenience sample of patients in outpatient settings (ie, emergency department, urgent care, and primary care) who were symptomatic, aged 1 year or older, and had suspected ARI and fever within 72 hours. Individuals with immunocompromised state and recent vaccine, antibiotics, stroke, surgery, major burn, or myocardial infarction were excluded. Of 1685 individuals assessed for eligibility, 259 individuals declined participation, 718 individuals were excluded, and 708 individuals were enrolled (520 patients with ARI, 170 patients without ARI, and 18 individuals who dropped out)., Exposures: Bacterial and viral immunoassay testing was performed using finger-stick blood. Results were read at 10 minutes, and treating clinicians and adjudicators were blinded to results., Main Outcomes and Measures: Bacterial- or viral-associated systemic host response to an ARI as determined by a predefined comparator algorithm with adjudication classified infection etiology., Results: Among 520 participants with ARI (230 male patients [44.2%] and 290 female patients [55.8%]; mean [SD] age, 35.3 [17.7] years), 24 participants with missing laboratory information were classified as unknown (4.6%). Among 496 participants with a final diagnosis, 73 individuals (14.7%) were classified as having a bacterial-associated response, 296 individuals (59.7%) as having a viral-associated response, and 127 individuals (25.6%) as negative by the reference standard. The bacterial and viral test correctly classified 68 of 73 bacterial infections, demonstrating a sensitivity of 93.2% (95% CI, 84.9%-97.0%), specificity of 374 of 423 participants (88.4% [95% CI, 85.0%-91.1%]), positive predictive value (PPV) of 68 of 117 participants (58.1% [95% CI, 49.1%-66.7%), and negative predictive value (NPV) of 374 of 379 participants (98.7% [95% CI, 96.9%-99.4%]).The test correctly classified 208 of 296 viral infections, for a sensitivity of 70.3% (95% CI, 64.8%-75.2%), a specificity of 176 of 200 participants (88.0% [95% CI, 82.8%-91.8%]), a PPV of 208 of 232 participants (89.7% [95% CI, 85.1%-92.9%]), and an NPV of 176 of 264 participants (66.7% [95% CI, 60.8%-72.1%])., Conclusions and Relevance: In this study, a rapid diagnostic test demonstrated diagnostic performance that may inform clinicians when assessing for bacterial or viral etiology of ARI symptoms.

Background: The purpose of the systematic review is to evaluate the efficacy and safety of sublingual immunotherapy (SLIT) for the treatment of allergic asthma., Methods: PubMed, Embase, and CENTRAL databases were searched, updating an earlier review (January 1, 2005 through May 8, 2017). Randomized, controlled studies (RCTs) were included, which reported one of the prespecified outcomes: asthma symptoms measured by control composite scores; quality of life; medication use; pulmonary physiology; and health-care utilization. For safety outcomes, RCTs and observational studies were included. Two independent reviewers extracted data, assessed risk of bias, and graded strength of evidence (SOE) for each outcome., Results: Fourteen RCTs (n = 2585) assessed the efficacy of SLIT for asthma. The RCTs utilized house dust mite (HDM), birch, or grass allergen. SLIT improved asthma symptoms (high SOE), decreased use of long-term control medication, and improved forced expiratory volume in 1 second (FEV 1 ) (moderate SOE). SLIT may decrease quick-relief medication use, and improve disease-specific quality of life (low SOE). For safety, 20 RCTs and 10 observational studies (n = 3621) were identified. Local (risk differences ranged from -0.03 to +0.765) and systemic allergic reactions (risk differences ranged from -0.03 to +0.06) were a common occurrence in SLIT and control groups. Life-threatening reactions were uncommon, with 3 cases of anaphylaxis and no deaths reported., Conclusion: There is moderate-to-high strength evidence that SLIT improves allergic asthma symptoms, reduces long-term control medication use, and improves FEV 1 based on studies of HDM, birch, and grass. SLIT rarely is associated with life-threatening adverse events., (© 2018 ARS-AAOA, LLC.)

Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Context: Treatment options for allergic asthma include allergen avoidance, pharmacotherapy, and allergen immunotherapy., Objectives: Summarize and update current evidence for the efficacy and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in pediatric allergic asthma., Data Sources: PubMed, Embase, Cochrane Central Register of Controlled Trials (January 1, 2005, through May 8, 2017), ClinicalTrials.gov, and the US Food and Drug Administration Adverse Event Reporting System. We reevaluated trials from our 2013 systematic review., Study Selection: We included studies with children ≤18 years of age in which researchers reported on prespecified outcomes and had an intervention arm receiving aeroallergen SCIT or SLIT. Only randomized controlled trials (RCTs) were included for efficacy. RCTs and non-RCTs were included for safety outcomes., Data Extraction: Two reviewers extracted data. We included 40 studies (17 SCIT trials, 11 SLIT trials, 8 non-RCTs for SCIT safety, and 4 non-RCTs for SLIT safety)., Results: We found moderate-strength evidence that SCIT reduces long-term asthma medication use. We found low-strength evidence that SCIT improves asthma-related quality of life and forced expiratory volume in 1 second. There was also low-strength evidence that SLIT improves medication use and forced expiratory volume in 1 second. There was insufficient evidence on asthma symptoms and health care use., Limitations: There were no trials in which researchers evaluated asthma symptoms using a validated tool. Study characteristics and outcomes were reported heterogeneously., Conclusions: In children with allergic asthma, SCIT may reduce long-term asthma medication use. Local and systemic allergic reactions are common, but anaphylaxis is reported rarely., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background: Patient and family engagement (PFE) is critical for patient safety. We systematically reviewed types of PFE strategies implemented and their impact on medication safety., Methods: We searched MEDLINE, EMBASE, reference lists and websites to August 2016. Two investigators independently reviewed all abstracts and articles, and articles were additionally reviewed by two senior investigators for selection. One investigator abstracted data and two investigators reviewed the data for accuracy. Study quality was determined by consensus. Investigators developed a framework for defining the level of patient engagement: informing patients about medications (Level 1), informing about engagement with health care providers (Level 2), empowering patients with communication tools and skills (Level 3), partnering with patients in their care (Level 4), and integrating patients as full care team members (Level 5)., Results: We included 19 studies that mostly targeted older adults taking multiple medications. The median level of engagement was 2, ranging from 2-4. We identified no level 5 studies. Key themes for patient engagement strategies impacting medication safety were patient education and medication reconciliation, with a subtheme of patient portals. Most studies (84%) reported implementation outcomes. The most commonly reported medication safety outcomes were medication errors, including near misses and discrepancies (47%), and medication safety knowledge (37%). Most studies (63%) were of medium to low quality, and risk of bias was generally moderate. Among the 11 studies with control groups, 55% (n = 6) reported statistically significant improvement on at least one medication safety outcome. Further synthesis of medication safety measures was limited due to intervention and outcome heterogeneity., Conclusions: Key strategies for engaging patients in medication safety are education and medication reconciliation. Patient engagement levels were generally low, as defined by a novel framework for determining levels of patient engagement. As more patient engagement studies are conducted, this framework should be evaluated for associations with patient outcomes.

The correct title of the article [1] should be "Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol".

Correction: The correct title of the article [1] should be "Integrating multiple data sources (MUDS) for meta-analysis to improve patient-centered outcomes research: a protocol". The article is a protocol for a methodological study, not a systematic review.

Objectives: The objective of this study was to determine whether disagreements among multiple data sources affect systematic reviews of randomized clinical trials (RCTs)., Study Design and Setting: Eligible RCTs examined gabapentin for neuropathic pain and quetiapine for bipolar depression, reported in public (e.g., journal articles) and nonpublic sources (clinical study reports [CSRs] and individual participant data [IPD])., Results: We found 21 gabapentin RCTs (74 reports, 6 IPD) and 7 quetiapine RCTs (50 reports, 1 IPD); most were reported in journal articles (18/21 [86%] and 6/7 [86%], respectively). When available, CSRs contained the most trial design and risk of bias information. CSRs and IPD contained the most results. For the outcome domains "pain intensity" (gabapentin) and "depression" (quetiapine), we found single trials with 68 and 98 different meta-analyzable results, respectively; by purposefully selecting one meta-analyzable result for each RCT, we could change the overall result for pain intensity from effective (standardized mean difference [SMD] = -0.45; 95% confidence interval [CI]: -0.63 to -0.27) to ineffective (SMD = -0.06; 95% CI: -0.24 to 0.12). We could change the effect for depression from a medium effect (SMD = -0.55; 95% CI: -0.85 to -0.25) to a small effect (SMD = -0.26; 95% CI: -0.41 to -0.1)., Conclusions: Disagreements across data sources affect the effect size, statistical significance, and interpretation of trials and meta-analyses., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Rapid improvements in hepatitis C virus (HCV) therapy have led to the approval of multiple oral direct-acting antiviral (DAA) regimens by the U.S. Food and Drug Administration (FDA) for treatment of chronic HCV infection., Purpose: To summarize published literature on the efficacy and safety of oral DAAs for treatment of persons with chronic HCV infection., Data Sources: MEDLINE and EMBASE from inception through 1 November 2016., Study Selection: 42 English-language studies from controlled and single-group registered clinical trials of adults with HCV infection that evaluated at least 8 weeks of an FDA-approved interferon-free HCV regimen that included at least 2 DAAs., Data Extraction: Two investigators abstracted data on study design, patient characteristics, and virologic and safety outcomes sequentially and assessed quality independently., Data Synthesis: Six DAA regimens showed high sustained virologic response (SVR) rates (>95%) in patients with HCV genotype 1 infection without cirrhosis, including those with HIV co-infection. Effective treatments for HCV genotype 3 infection are limited (2 DAA regimens). Patients with hepatic decompensation, particularly those with Child-Turcotte-Pugh class C disease, had lower SVR rates (78% to 87%) than other populations. The addition of ribavirin was associated with increased SVR rates for certain DAA regimens and patient groups. Overall rates of serious adverse events and treatment discontinuation were low (<10% in the general population); regimens that included ribavirin had more mild or moderate adverse events than those without., Limitations: Twenty-three studies had moderate risk of bias (10 were open-label single-group trials, 11 had limited information on concealment of the allocation scheme, and 5 had selective outcome reporting). All but 1 of the studies were industry-funded. Heterogeneity of interventions precluded pooling., Conclusion: Multiple oral DAA regimens show high rates of safety, tolerability, and efficacy for treatment of HCV genotype 1 infection, particularly among persons without cirrhosis., Primary Funding Source: Patient-Centered Outcomes Research Institute. (PROSPERO: CRD42014009711).

Background: Clinicians and patients need updated evidence on the comparative effectiveness and safety of diabetes medications to make informed treatment choices., Purpose: To evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes., Data Sources: English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE search updated through December 2015)., Study Selection: Paired reviewers independently identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations., Data Extraction: Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence., Data Synthesis: Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors., Limitation: Most studies were short, with limited ability to assess rare safety and long-term clinical outcomes., Conclusion: The evidence supports metformin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: Iodine contrast media are essential components of many imaging procedures. An important potential side effect is contrast-induced nephropathy (CIN)., Purpose: To compare CIN risk for contrast media within and between osmolality classes in patients receiving diagnostic or therapeutic imaging procedures., Data Sources: PubMed, EMBASE, Cochrane Library, Clinical Trials.gov, and Scopus through June 2015., Study Selection: Randomized, controlled trials that reported CIN-related outcomes in patients receiving low-osmolar contrast media (LOCM) or iso-osmolar contrast media for imaging., Data Extraction: Independent study selection and quality assessment by 2 reviewers and dual extraction of study characteristics and results., Data Synthesis: None of the 5 studies that compared types of LOCM reported a statistically significant or clinically important difference among study groups, but the strength of evidence was low. Twenty-five randomized, controlled trials found a slight reduction in CIN risk with the iso-osmolar contrast media agent iodixanol compared with a diverse group of LOCM that just reached statistical significance in a meta-analysis (pooled relative risk, 0.80 [95% CI, 0.65 to 0.99]; P = 0.045). This comparison's strength of evidence was moderate. In a meta regression of randomized, controlled trials of iodixanol, no relationship was found between route of administration and comparative CIN risk., Limitations: Few studies compared LOCM. Procedural details about contrast administration were not uniformly reported. Few studies specified clinical indications or severity of baseline renal impairment., Conclusion: No differences were found in CIN risk among types of LOCM. Iodixanol had a slightly lower risk for CIN than LOCM, but the lower risk did not exceed a criterion for clinical importance., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: N-acetylcysteine, sodium bicarbonate, statins, and ascorbic acid have been studied for reducing contrast-induced nephropathy (CIN)., Purpose: To evaluate the comparative effectiveness of interventions to reduce CIN in adults receiving contrast media., Data Sources: MEDLINE, EMBASE, Cochrane Library, ClinicalTrials.gov, and Scopus databases through June 2015. Risk of bias and overall strength of evidence (SOE) of studies were assessed., Study Selection: Randomized, controlled trials of N-acetylcysteine, sodium bicarbonate, statins, or ascorbic acid that used intravenous (IV) or intra-arterial contrast media and defined CIN with enough data for meta-analysis., Data Extraction: Two reviewers independently extracted data and assessed study quality., Data Synthesis: Low-dose N-acetylcysteine plus IV saline compared with IV saline (risk ratio [RR], 0.75 [95% CI, 0.63 to 0.89]; low SOE), N-acetylcysteine plus IV saline compared with IV saline in patients receiving low-osmolar contrast media (RR, 0.69 [CI, 0.58 to 0.84]; moderate SOE), and statins plus N-acetylcysteine plus IV saline versus N-acetylcysteine plus IV saline (RR, 0.52 [CI, 0.29 to 0.93]; low SOE) had clinically important and statistically significant benefits. The following 3 comparisons suggested a clinically important difference that was not statistically significant: sodium bicarbonate versus IV saline in patients receiving low-osmolar contrast media (RR, 0.65 [CI, 0.33 to 1.25]; low SOE), statins plus IV saline versus IV saline (RR, 0.68 [CI, 0.39 to 1.20]; low SOE), and ascorbic acid versus IV saline (RR, 0.72 [CI, 0.48 to 1.01]; low SOE). Strength of evidence was generally insufficient for comparisons of the need for renal replacement, cardiac events, and mortality., Limitation: Too few studies were done in patients receiving IV contrast media., Conclusion: The greatest reduction in CIN was seen with N-acetylcysteine plus IV saline in patients receiving LOCM and with statins plus N-acetylcysteine plus IV saline., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: Systematic reviews should provide trustworthy guidance to decision-makers, but their credibility is challenged by the selective reporting of trial results and outcomes. Some trials are not published, and even among clinical trials that are published partially (e.g., as conference abstracts), many are never published in full. Although there are many potential sources of published and unpublished data for systematic reviews, there are no established methods for choosing among multiple reports or data sources about the same trial., Methods: We will conduct systematic reviews of the effectiveness and safety of two interventions following the Institute of Medicine (IOM) guidelines: (1) gabapentin for neuropathic pain and (2) quetiapine for bipolar depression. For the review of gabapentin, we will include adult participants with neuropathic pain who do not require ventilator support. For the review of quetiapine, we will include adult participants with acute bipolar depression (excluding mixed or rapid cycling episodes). We will compare these drugs (used alone or in combination with other interventions) with placebo or with the same intervention alone; direct comparisons with other medications will be excluded. For each review, we will conduct highly sensitive electronic searches, and the results of the searches will be assessed by two independent reviewers. Outcomes, study characteristics, and risk of bias ratings will be extracted from multiple reports by two individuals working independently, stored in a publicly available database (Systematic Review Data Repository) and analyzed using commonly available statistical software. In each review, we will conduct a series of meta-analyses using data from different sources to determine how the results are affected by the inclusion of data from multiple published sources (e.g., journal articles and conference abstracts) as well as unpublished aggregate data (e.g., "clinical study reports") and individual participant data (IPD). We will identify patient-centered outcomes in each report and identify differences in the reporting of these outcomes across sources., Systematic Review Registration: CRD42015014037 , CRD42015014038.

This systematic review identifies possible decision aids that promote perioperative advance care planning (ACP) and synthesizes the available evidence regarding their use. Using PubMed, EMBASE, Cochrane, SCOPUS, Web of Science, CINAHL, PsycINFO and Sociological Abstracts, researchers identified and screened articles for eligibility. Data were abstracted and risk of bias assessed for included articles. Thirty-nine of 5327 articles satisfied the eligibility criteria. Primarily completed in outpatient ambulatory populations, studies evaluated a variety of ACP decision aids. None were evaluated in a perioperative population. Fifty unique outcomes were reported with no head-to-head comparisons conducted. Findings are likely generalizable to a perioperative population and can inform development of a perioperative ACP decision aid. Future studies should compare the effectiveness of ACP decision aids.

Objective: Surgical site infections (SSIs) are a leading cause of morbidity and mortality among women undergoing cesarean section (C-section), a common procedure in North America. While risk factors for SSI are often modifiable, wide variation in clinical practice exists. With this review, we provide a comprehensive overview of the results and quality of systematic reviews and meta-analyses on interventions to reduce surgical site infections among women undergoing C-section., Methods: We searched PubMed and the Cochrane Database of Systematic Reviews for systematic reviews and meta-analyses published between January 2000 and May 2014 on interventions to reduce the occurrence of SSIs (incisional infections and endometritis), among women undergoing C-section. We extracted data on the interventions, outcomes, and strength of evidence as determined by the original article authors, and assessed the quality of each article based on a modified Assessment of Multiple Systematic Reviews tool., Results: A total of 30 review articles met inclusion criteria and were reviewed. Among these articles, 77 distinct interventions were evaluated: 29% were supported with strong evidence as assessed by the original article authors, and 83% of the reviews articles were classified as good quality based on our assessment. Ten interventions were classified as being effective in reducing SSI with strong evidence in a good-quality article, including preoperative vaginal cleansing, the use of perioperative antibiotic prophylaxis, and several surgical techniques., Conclusion: Efforts to reduce SSI rates among women undergoing C-section should include interventions such as preoperative vaginal cleansing and the use of perioperative antibiotics because compelling evidence exists to support their effectiveness.

Background: Patients with chronic kidney disease (CKD) have high prevalence of elevated serum troponin levels, which makes diagnosis of acute coronary syndrome (ACS) challenging., Purpose: To evaluate the utility of troponin in ACS diagnosis, treatment, and prognosis among patients with CKD., Data Sources: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through May 2014., Study Selection: Studies examining elevated versus normal troponin levels in terms of their diagnostic performance in detection of ACS, effect on ACS management strategies, and prognostic value for mortality or cardiovascular events after ACS among patients with CKD., Data Extraction: Paired reviewers selected articles for inclusion, extracted data, and graded strength of evidence (SOE)., Data Synthesis: Twenty-three studies met inclusion criteria. The sensitivity of troponin T for ACS diagnosis ranged from 71% to 100%, and specificity ranged from 31% to 86% (6 studies; low SOE). The sensitivity and specificity of troponin I ranged from 43% to 94% and from 48% to 100%, respectively (8 studies; low SOE). No studies examined how troponin levels affect management strategies. Twelve studies analyzed prognostic value. Elevated levels of troponin I or troponin T were associated with higher risk for short-term death and cardiac events (low SOE). A similar trend was observed for long-term mortality with troponin I (low SOE), but less evidence was found for long-term cardiac events for troponin I and long-term outcomes for troponin T (insufficient SOE). Patients with advanced CKD tended to have worse prognoses with elevated troponin I levels than those without them (moderate SOE)., Limitation: Studies were heterogeneous in design and in ACS definitions and adjudication methods., Conclusion: In patients with CKD and suspected ACS, troponin levels can aid in identifying those with a poor prognosis, but the diagnostic utility is limited by varying estimates of sensitivity and specificity., Primary Funding Source: Agency for Healthcare Research and Quality.

Background: Clinicians face uncertainty about the prognostic value of troponin testing in patients with chronic kidney disease (CKD) without suspected acute coronary syndrome (ACS)., Purpose: To systematically review the literature on troponin testing in patients with CKD without ACS., Data Sources: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through May 2014., Study Selection: Studies examining elevated versus normal troponin levels in patients with CKD without ACS., Data Extraction: Paired reviewers selected articles for inclusion, extracted data, and graded strength of evidence (SOE). Meta-analyses were conducted when studies had sufficient homogeneity of key variables., Data Synthesis: Ninety-eight studies met inclusion criteria. Elevated troponin levels were associated with all-cause and cardiovascular mortality among patients receiving dialysis (moderate SOE). Pooled hazard ratios (HRs) for all-cause mortality from studies that adjusted for age and coronary artery disease or a risk equivalent were 3.0 (95% CI, 2.4 to 4.3) for troponin T and 2.7 (CI, 1.9 to 4.6) for troponin I. The pooled adjusted HRs for cardiovascular mortality were 3.3 (CI, 1.8 to 5.4) for troponin T and 4.2 (CI, 2.0 to 9.2) for troponin I. Findings were similar for patients with CKD who were not receiving dialysis, but there were fewer studies. No study tested treatment strategies by troponin cut points., Limitation: Studies were heterogeneous regarding assays, troponin cut points, covariate adjustment, and follow-up., Conclusion: In patients with CKD without suspected ACS, elevated troponin levels were associated with worse prognosis. Future studies should focus on whether this biomarker is more appropriate than clinical models for reclassifying risk of patients with CKD and whether such classification can help guide treatment in those at highest risk for death., Primary Funding Source: Agency for Healthcare Research and Quality.

Objectives/hypothesis: To systematically review the effectiveness and safety of subcutaneous immunotherapy (SCIT) for treatment of allergic rhinoconjunctivitis and asthma, using formulations currently approved in the United States., Study Design: We searched the following databases up to May 21, 2012: MEDLINE, Embase, LILACS, and the Cochrane Central Register of Controlled Trials., Methods: We included randomized controlled trials published in English comparing SCIT to placebo, pharmacotherapy, or other SCIT regimens that reported clinical outcomes of interest. Studies of adults or mixed age populations were included. Studies were excluded if the diagnosis of allergy and/or asthma was not confirmed with objective testing. Paired reviewers selected articles for inclusion and extracted data. We assessed the risk of bias for each study and graded the strength of evidence for each outcome as high, moderate, or low., Results: Sixty-one studies met our inclusion criteria. Majority of the studies (66%) evaluated single-allergen immunotherapy regimens. The literature provides high-grade evidence that SCIT reduces asthma symptoms, asthma medication usage, rhinitis/rhinoconjunctivitis symptoms, conjunctivitis symptoms, and rhinitis/rhinoconjunctivitis disease-specific quality of life in comparison to placebo or usual care. There is moderate evidence that SCIT decreases rhinitis/rhinoconjunctivitis medication usage. Respiratory reactions were the most common systemic reaction. There were few reports of anaphylaxis; no deaths were reported., Conclusions: Generally moderate to strong evidence supports the effectiveness of SCIT for treatment of allergic rhinitis and asthma, particularly with single-allergen immunotherapy regimens. Adverse reactions to SCIT are common, but no deaths were reported in the included studies., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Allergen-specific immunotherapy is widely used in the management of patients with allergic rhinoconjunctivitis and asthma, but the best route of delivery is unclear., Objective: We performed a systematic review of studies with head-to-head comparison of effectiveness and safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) in the treatment of allergic rhinoconjunctivitis and asthma., Methods: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials databases were searched through December 21, 2012. We included English language randomized controlled trials that enrolled patients with allergic rhinoconjunctivitis and/or asthma with head-to-head comparisons of SCIT with SLIT. Paired reviewers extracted detailed information from included articles on standardized forms and assessed the risk of bias in each article., Results: Eight trials compared the effectiveness and safety of SCIT and SLIT. The effectiveness of the 2 forms of immunotherapy in managing allergic asthma and rhinoconjunctivitis were reported in 4 and 6 clinical trials, respectively. Low-grade evidence supports greater effectiveness of SCIT than SLIT for asthma symptom reduction and also at reducing a combined measure of rhinitis symptoms and medication use. Moderate-grade evidence supports greater effectiveness of SCIT than SLIT for nasal and/or eye symptom reduction. All 8 trials reported on adverse events with an episode of anaphylaxis reported in a child treated with SCIT., Conclusion: Our review provides low-grade evidence to support that SCIT is superior to SLIT for reduction in asthma symptoms and moderate-grade evidence for reduction of allergic rhinoconjunctivitis. Additional studies are required to strengthen this evidence base for clinical decision making., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Subcutaneous immunotherapy (SCIT) is approved in the United States for the treatment of pediatric asthma and rhinitis; sublingual immunotherapy (SLIT) does not have regulatory approval but is used in clinical practice. The objective of this study was to systematically review the evidence regarding the efficacy and safety of SCIT and SLIT for the treatment of pediatric asthma and allergic rhinoconjunctivitis., Methods: Two independent reviewers selected articles for inclusion, extracted data, and graded the strength of evidence for each clinical outcome. All studies were randomized controlled trials of children with allergic asthma or rhinoconjunctivitis treated with SCIT or an aqueous formulation of SLIT. Data sources were Medline, Embase, LILACS, CENTRAL, and the Cochrane Central Register of Controlled Trials through May 2012., Results: In 13 trials, 920 children received SCIT or usual care; in 18 studies, 1583 children received SLIT or usual care. Three studies compared SCIT with SLIT head-to-head in 135 children. The strength of evidence is moderate that SCIT improves asthma and rhinitis symptoms and low that SCIT improves conjunctivitis symptoms and asthma medication scores. Strength of evidence is high that SLIT improves asthma symptoms and moderate that SLIT improves rhinitis and conjunctivitis symptoms and decreases medication usage. The evidence is low to support SCIT over SLIT for improving asthma or rhinitis symptoms or medication usage. Local reactions were frequent with SCIT and SLIT. There was 1 report of anaphylaxis with SCIT., Conclusions: Evidence supports the efficacy of both SCIT and SLIT for the treatment of asthma and rhinitis in children.

Importance: Allergic rhinitis affects up to 40% of the US population. To desensitize allergic individuals, subcutaneous injection immunotherapy or sublingual immunotherapy may be administered. In the United States, sublingual immunotherapy is not approved by the Food and Drug Administration. However, some US physicians use aqueous allergens, off-label, for sublingual desensitization., Objective: To systematically review the effectiveness and safety of aqueous sublingual immunotherapy for allergic rhinoconjunctivitis and asthma., Evidence Acquisition: The databases of MEDLINE, EMBASE, LILACS, and the Cochrane Central Register of Controlled Trials were searched through December 22, 2012. English-language randomized controlled trials were included if they compared sublingual immunotherapy with placebo, pharmacotherapy, or other sublingual immunotherapy regimens and reported clinical outcomes. Studies of sublingual immunotherapy that are unavailable in the United States and for which a related immunotherapy is unavailable in the United States were excluded. Paired reviewers selected articles and extracted the data. The strength of the evidence for each comparison and outcome was graded based on the risk of bias (scored on allocation, concealment of intervention, incomplete data, sponsor company involvement, and other bias), consistency, magnitude of effect, and the directness of the evidence., Results: Sixty-three studies with 5131 participants met the inclusion criteria. Participants' ages ranged from 4 to 74 years. Twenty studies (n = 1814 patients) enrolled only children. The risk of bias was medium in 43 studies (68%). Strong evidence supports that sublingual immunotherapy improves asthma symptoms, with 8 of 13 studies reporting greater than 40% improvement vs the comparator. Moderate evidence supports that sublingual immunotherapy use decreases rhinitis or rhinoconjunctivitis symptoms, with 9 of 36 studies demonstrating greater than 40% improvement vs the comparator. Medication use for asthma and allergies decreased by more than 40% in 16 of 41 studies of sublingual immunotherapy with moderate grade evidence. Moderate evidence supports that sublingual immunotherapy improves conjunctivitis symptoms (13 studies), combined symptom and medication scores (20 studies), and disease-specific quality of life (8 studies). Local reactions were frequent, but anaphylaxis was not reported., Conclusions and Relevance: The overall evidence provides a moderate grade level of evidence to support the effectiveness of sublingual immunotherapy for the treatment of allergic rhinitis and asthma, but high-quality studies are still needed to answer questions regarding optimal dosing strategies. There were limitations in the standardization of adverse events reporting, but no life-threatening adverse events were noted in this review.

Background: Glaucoma is an acquired degeneration of the optic nerve and a leading cause of blindness worldwide. Medical and surgical treatments that decrease intraocular pressure may prevent visual impairment and blindness., Purpose: To compare the effectiveness of medical, laser, and surgical treatments in adults with open-angle glaucoma with regard to decreasing intraocular pressure and preventing optic nerve damage, vision loss, and visual impairment., Data Sources: MEDLINE, CENTRAL, and an existing database for systematic reviews (through 2 March 2011); MEDLINE, EMBASE, LILACS, and CENTRAL for primary studies (through 30 July 2012)., Study Selection: English-language systematic reviews; randomized, controlled trials; and quasi-randomized, controlled trials for most outcomes and observational studies for quality of life and harms., Data Extraction: Two investigators abstracted or checked information about study design, participants, and outcomes and assessed risk of bias and strength of evidence., Data Synthesis: High-level evidence suggests that medical, laser, and surgical treatments decrease intraocular pressure and that medical treatment and trabeculectomy reduce the risk for optic nerve damage and visual field loss compared with no treatment. The direct effect of treatments on visual impairment and the comparative efficacy of different treatments are not clear. Harms of medical treatment are primarily local (ocular redness, irritation); surgical treatment carries a small risk for more serious complications., Limitation: Heterogeneous outcome definitions and measurements among the included studies; exclusion of many treatment studies that did not stratify results by glaucoma type., Conclusion: Medical and surgical treatments for open-angle glaucoma lower intraocular pressure and reduce the risk for optic nerve damage over the short to medium term. Which treatments best prevent visual disability and improve patient-reported outcomes is unclear.

We have previously shown that expanded/activated γδ T cells from healthy donors are cytotoxic to GBM cell lines and primary GBM explants. In this report, we examined the therapeutic effect of intracranial infusion of expanded/activated γδ T cells on human minimal and established U251 tumor xenografts in athymic nude mice. Immunohistochemistry was used to determine the presence of NKG2D ligands on cell lines and tumors, and blocking studies were used to determine the effect of these ligands on γδ T cell recognition. Expanded/activated γδ T cells were prepared by 18-day culture in RPMI, human serum (HS), anti-CD2, IL-12, IFN-γ, and OKT-3. Anti-GBM activity of the cell product was assessed using in vitro cytotoxicity assays against the GBM cell line U251MG in suspension and in adherent culture. Ex vivo expanded/activated γδ T cells were of the effector/memory phenotype, expressed Th1 cytokines, and effectively killed U251 cells in vitro. Xenografts were prepared using a U251 cell line following transfection with a firefly luciferase gene to monitor tumor progression. Mice treated with γδ T cells showed slower progression of both new and established GBM xenografts versus mice that received vehicle only as determined by photon emission over time. Median survival was improved in all γδ T cell treated groups between 32 and 50 days by Kaplan-Meier analysis. U251 cells expressed ULBP-2 and ULBP-3, although blocking of these reduced in vitro cytotoxicity of γδ T cells to U251MG by only 33 and 25%, respectively. These studies show that expanded/activated γδ T cells can mediate killing of new or established GBM xenografts, reduce tumor progression, and constitute a potentially effective novel immunotherapeutic strategy against GBM.

Objective: Since the anti-tumor activity of 5-fluorouracil (5-FU) is due to induction of apoptosis, we assessed the value of expression of key apoptotic molecules (Bax, Bcl-2 and p53) in predicting the efficacy of 5-FU therapy for colorectal adenocarcinomas (CRCs)., Methods: Archival tissues of CRCs from 56 patients who received a complete regimen of 5-FU-based chemotherapy after surgery, and 56 patients matched for age, gender, ethnicity, tumor stage, tumor location, and tumor differentiation who had undergone only surgery (without any pre- or post-surgery therapy), were evaluated for immunophenotypic expression of Bax, Bcl-2, and p53. Also, these CRCs were evaluated for Bax mutations. The predictive capacity or prognostic value of these markers was assessed by estimating overall survival., Results: The majority of low Bax expressing CRCs have exhibited mutations at the G (8) tract. There was no significant difference in overall survival rates between the categories of surgery alone and 5-FU-treated patients. However, a better survival was observed for patients who received chemotherapy when their CRCs had low Bax/Bcl2 ratio (HR, 1.55; 95% CI: 1.46-31.00). Patients who received surgery alone and whose CRCs lacked Bax expression had 5.33 times higher mortality than those with high Bax expression (95% CI: 1.78-15.94), when controlled for tumor stage and other confounders. Bcl-2 and nuclear p53 accumulation had no predictive value in either patient group., Conclusion: These findings are the first to demonstrate that high Bax expression is a good prognosticator for patients who underwent surgery alone, and that patient with low Bax/Bcl-2 expression ratio benefit from 5-FU-based adjuvant therapies.

Classical immunotherapeutic approaches to glioblastoma multiforme (GBM) have shown mixed results, and therapies focused on innate lymphocyte activity against GBM have not been rigorously evaluated. We examined peripheral blood lymphocyte phenotype, gammadelta T-cell number, mitogenic response, and cytotoxicity against GBM cell lines and primary tumor explants from GBM patients at selected time points prior to and during GBM therapy. Healthy volunteers served as controls and were grouped by age. T-cell infiltration of tumors from these patients was assessed by staining for CD3 and T-cell receptor gammadelta. Our findings revealed no differences in counts of mean absolute T-cells, T-cell subsets CD3+CD4+ and CD3+CD8+, and natural killer cells from healthy volunteers and patients prior to and immediately after GBM resection. In contrast, gammadelta T-cell counts and mitogen-stimulated proliferative response of gammadelta T-cells were markedly decreased prior to GBM resection and throughout therapy. Expanded/activated gammadelta T-cells from both patients and healthy volunteers kill GBM cell lines D54, U373, and U251, as well as primary GBM, without cytotoxicity to primary astrocyte cultures. Perivascular T-cell accumulation was noted in paraffin sections, but no organized T-cell invasion of the tumor parenchyma was seen. Taken together, these data suggest that gammadelta T-cell depletion and impaired function occur prior to or concurrent with the growth of the tumor. The significant cytotoxicity of expanded/activated gammadelta T-cells from both healthy controls and selected patients against primary GBM explants may open a previously unexplored approach to cellular immunotherapy of GBM.

Purpose: Although the decreased expression of p27(kip-1), a cyclin-dependent kinase inhibitor, has been correlated with advanced tumor stage and short survival of patients with colorectal adenocarcinomas (CRCs), its prognostic value based on the tumor site, tumor stage, and patient ethnicity was not assessed. Therefore, in this study, we investigated whether the prognostic value of p27(kip-1) expression varies with the tumor site, tumor stage and patient ethnicity., Experimental Design: We evaluated 206 (85 African Americans and 121 Caucasians) archival tissue specimens of first primary CRCs for immunohistochemical expression of p27(kip-1), and its prognostic significance was analyzed using univariate Kaplan-Meier and multivariate Cox regression survival methods., Results: Although, similar proportion of CRCs with decreased p27(kip-1) expression was observed in all stages (range, 26-36%), the decreased p27(kip-1) expression has been shown as a marker of poor prognosis only for patients with stage III tumors both in univariate (log-rank test, P = 0.014) and multivariate (hazard ratio = 3.2, 95% confidence interval = 1.3-7.7; P = 0.01) survival analyses. The decreased expression of p27(kip-1) was associated with a high histologic grade (P = 0.016) in stage II CRCs, and with distal tumors (P = 0.001), tumor invasion (P = 0.044), and with local recurrence (P = 0.008) in stage III CRCs., Conclusions: No prognostic significance was found for p27(kip-1) expression in stages I, II, or IV CRCs, and its prognostic value was not associated with either ethnicity or tumor location. These studies suggest that decreased expression of p27(kip-1) is an indicator of poor prognosis and aids in identifying a subset of patients with aggressive forms of stage III CRCs.

p38 belongs to a family of mitogen-activated protein kinases, which transfer extracellular signals into intracellular responses. p38 is also frequently detected in clinical breast cancer specimens, but its role as a prognostic factor is not known. Of the various p38 isoforms, p38alpha has been shown to mediate the in vitro invasiveness of breast cancer cells through up-regulation of urokinase plasminogen activator (uPA). We studied the role of p38alpha in breast cancer bone metastases, using dominant negative blockade approach. Human MDA-MB-231 breast cancer clones stably expressing dominant negative p38alpha (p38/AF) exhibited decreased basal MMP-9 activity. TGF-beta1-induced MMP-9 activity was also blunted in these clones, as compared with controls in which TGF-betal up-regulated MMP-9 activity. Consistent with these findings, SB202190, a specific p38 inhibitor, also inhibited TGF-beta1-induced MMP-9 activity in parental cells. The p38/AF clones exhibited also reduced uPA production after growth on vitronectin and decreased cell motility, as compared with controls. VEGF production levels in all the studied clones were similar. The p38/AF clone, which had similar in vitro growth rate as the control pcDNA3 clone, formed significantly less bone metastases in a mouse model, as compared with the control clone. In conclusion, inhibition of the p38alpha pathway results in decreased MMP-9 activity, impaired uPA expression and decreased motility, all of which may contribute to the decreased formation of bone metastasis.

Bisphosphonates (BPs) inhibit osteoclast-mediated bone resorption. They also protect from cancer-induced osteolysis and inhibit breast cancer growth in vitro. Some breast cancer cell lines, however, are relatively resistant to the growth inhibitory effects of BPs. We studied the mechanism of BP resistance in human MDA-MB-231 breast cancer cells. We show that both pyrophosphate-resembling (p-) and nitrogen-containing (n-) BPs induce activation of p38 mitogen activated protein (MAP) kinase pathway in MDA-MB-231 cells in vitro. MDA-MB-231 cells stably expressing a dominant negative form of the p38 MAP kinase (p38/AF) exhibited a dramatic increase in growth inhibition in response to BPs in vitro, compared to control cells. SB203580, a specific inhibitor of the p38 MAP kinase, also augmented BP-induced growth inhibition of parental MDA-MB-231 cells. Similar results were obtained also in murine macrophage-like J774 cells in vitro. Finally, no BP-induced phosphorylation of p38, or augmentation of BP-induced growth inhibition by SB203580 were detected in MCF-7 or HCC38 breast cancer cells, which are more sensitive than MDA-MB-231 cells especially to n-BP induced growth inhibition. In conclusion, these results suggest that BPs activate the p38 pathway in MDA-MB-231 and J774 cells. This activation may be associated with increased survival or proliferation because inhibition of p38 augments BP-induced growth inhibition. These findings may apply to the development of novel approaches for the treatment of breast cancer.

Interleukin-6 (IL-6) and interleukin-11 (IL-11) are frequently produced by breast cancer cells. These interleukins promote osteoclast formation and may mediate osteolysis at the site of breast cancer bone metastases. Transforming growth factor-beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) up-regulate IL-6 and IL-11 production in a cytokine-dependent fashion in breast cancer cells, but very little is known about their intracellular signaling pathways in breast cancer cells. To study TGF-beta, TNF-alpha and IL-1beta regulation of IL-6 and IL-11 production in human MDA-MB-231 breast cancer cells, we established single cell clones stably expressing dominant negative (DN) forms of the mitogen-activated protein kinases p38 (p38/AF) or ERK1 (ERK1K71R). We show here, that while basal, TGF-beta and IL-1beta induced IL-6 production was similar in parental cells and in pcDNA3 control, ERK1K71R and p38/AF clones, TNF-alpha induced IL-6 production was blunted in the ERK1K71R clones. TGF-beta and IL-1beta, but not TNF-alpha, induced IL-11 production in parental MDA-MB-231 cells. Similar findings were detected in clones stably expressing p38/AF and ERK1K71R, which did not change basal IL-11 production either. In conclusion, TNF-alpha induced IL-6 production is mediated via ERK1 activation in MDA-MB-231 cells. These observations may be helpful in designing new anti-osteolytic therapies.