Search

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 4 3% 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 identifying those with a poor prognosis, but the diagnostic utility is limited by varying estimates of sensitivity and specificity. [ABSTRACT FROM AUTHOR]

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% Cl, 2.4 to 4.3) for troponin T and 2.7 (Cl, 1.9 to 4.6) for troponin I. The pooled adjusted HRs for cardiovascular mortality were 3.3 (Cl, 1.8 to 5.4) for troponin T and 4.2 (Cl, 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-u p. 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. [ABSTRACT FROM AUTHOR]

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. Level of Evidence 1a. Laryngoscope, 124:616-627, 2014 [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article focuses on a study related to the use of sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma in the U.S. It informs that though sublingual immunotherapy is not approved by the U.S. Food and Drug Administration, yet some physicians use aqueous allergens for sublingual desensitization. Several databases and the Cochrane Central Register of Controlled Trials were searched. It also informs that overall evidence provides a moderate grade level of evidence to support the effectiveness of sublingual immunotherapy for the treatment of allergic rhinitis and asthma.

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 sur-gical 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 informa-tion 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 compara-tive 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 glau-coma 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. Primary Funding Source: Agency for Healthcare Research and Quality. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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, p38 β 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 p38 β in breast cancer bone metastases, using dominant negative blockade approach. Human MDA-MB-231 breast cancer clones stably expressing dominant negative p38 β (p38/AF) exhibited decreased basal MMP-9 activity. TGF- β 1-induced MMP-9 activity was also blunted in these clones, as compared with controls in which TGF- β 1 up-regulated MMP-9 activity. Consistent with these findings, SB202190, a specific p38 inhibitor, also inhibited TGF-β1-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 p38 β 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. [ABSTRACT FROM AUTHOR]

Two letters to the editor are presented in response to the article "Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review," published in the 2013 issue and also includes a response by the author regarding the same.

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”. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

Contains correspondence over proposed psychiatric training for family doctors. Structure of 8-week block rotation for the first and second years; Evidence of improvement of recognition skills by residents; Favorable treatment response of patients.