When first line therapy with metformin is insufficient for patients with type 2 diabetes (T2D), the optimal adjunctive therapy is unclear. We assessed the efficacy and safety of adjunctive antidiabetic agents in patients with inadequately controlled T2D on metformin alone.clinicaltrials.gov, regulatory websites was performed. We included randomized controlled trials of 3–12 months duration, evaluating Food and Drug Administration or European Union approved agents  in patients experiencing inadequate glycemic control with metformin monotherapy . Random-effects network meta-analyses were used to compare the weighted mean difference for changes from baseline in HbA1c, body weight (BW) and systolic blood pressure (SBP), and the risk of developing hypoglycemia, urinary (UTI) and genital tract infection (GTI).A search of MEDLINE and CENTRAL, Sixty-two trials evaluating 25 agents were included. All agents significantly reduced HbA1c vs. placebo; albeit not to the same extent . Glargine, sulfonylureas (SUs) and nateglinide were associated with increased hypoglycemia risk vs. placebo . Sodium glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 analogs, miglitol and empagliflozin/linagliptin significantly reduced BW  whereas SUs, thiazolindinediones, glargine and alogliptin/pioglitazone caused weight gain . SGLT2 inhibitors, empagliflozin/linagliptin, liraglutide and sitagliptin decreased SBP . No therapy increased UTI risk vs. placebo; however, SGLT2 inhibitors were associated with an increased risk of GTI .Adding different AHAs to metformin was associated with varying effects on HbA1c, BW, SBP, hypoglycemia, UTI and GTI which should impact clinician choice when selecting adjunctive therapy. The American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recommend lifestyle modifications and metformin as first-line therapy in type 2 diabetes mellitus (DM) . HoweverTraditional pair-wise meta-analysis can be used to evaluate the efficacy and safety of two drugs based on evidence from RCTs that directly compare them. However, in absence of such direct head-to-head comparisons, network meta-analysis (NMA) provides a statistical framework that incorporates evidence from both direct and indirect comparisons from a network of studies of different therapies and evaluates their relative treatment effects –4.We performed a NMA to assess the comparative efficacy and safety of adjunctive antidiabetic medication therapies in patients with Type 2 DM not adequately controlled on stable and optimized metformin monotherapy.www.clinicaltrials.gov, regulatory agency reports and by contacting investigators for clarification or additional data. Two investigators reviewed all potentially relevant citations independently .We performed a systematic literature search for all relevant articles from the earliest date through May 2014 in MEDLINE and Cochrane CENTRAL. The search strategy combined the Medical Subject Heading (MeSH) and keywords for “metformin” with terms for Type 2 DM and for glycosylated hemoglobin A1c (HbA1c). Our MEDLINE search strategy is included in To be included, studies had to: (1) be published in English; (2) utilize a parallel RCT design (any phase) in adults (≥18 years) with Type 2 DM; (3) compare Food and Drug Administration (FDA) or European Union (EU)-approved antidiabetic drug therapy including non-insulin and long-acting, once-daily basal insulin agents (as a single or combination adjunctive therapy) to another antidiabetic therapy or placebo (in addition to metformin); 4) include only patients who showed inadequate response to stable, optimized metformin monotherapy at randomization; (5) treat patients for 12 to 52 glycemic weeks after randomization; and (6) report change in HbA1c from baseline (our primary endpoint). As in previous NMAs [ include Validity assessment was performed by 2 investigators  independently using the Cochrane Risk of Bias Tool . This chTwo investigators  used a standardized tool to independently extract all data with disagreements resolved by discussion or a third investigator (CIC). The following information was sought from each trial: (1) author identification; 2) year of publication; (3) study design and methodological quality information needed to complete the Cochrane Collaboration’s tool for assessing risk of bias  year of ; (4) sam2 statistic with a value >50% representing important statistical heterogeneity) and publication bias (using the Egger’s weighted regression statistic with a P <0.05 suggesting a higher likelihood of publication bias) were assessed.We performed traditional meta-analyses analyzing changes in HbA1c, BW and SBP as continuous variables using StatsDirect version 2.7.8  with a P<0.05 considered statistically significant. Separate pair-wise analyses were performed for each antidiabetic therapy, combining data from approved doses of the same therapies using the method recommended by the Cochrane Collaboration [We then performed NMA, a generalization of traditional pairwise meta-analysis that compares all pairs of treatments within a set of treatments for the same disease state (in this case Type 2 DM) . Along wThe literature search yielded 1,005 citations, and we identified 17 additional RCTs through other sources . After rCharacteristics of the included trials are described in The SGLT2 inhibitors had similar effects on reducing HbA1c when compared to placebo in the NMA, ranging from 0.48% for dapagliflozin to 0.72% for canagliflozin . When coBoth combination agents were associated with significant reductions in HbA1c when compared to placebo in the NMA . When comparing the combination medications to the other active single agents, alogliptin/pioglitazone significantly reduced HbA1c when compared to all other therapies except for insulin glargine, glibenclamide and repaglinide; whereas empagliflozin/linagliptin was more efficacious when compared to all other active single agents except for insulin glargine, glibenclamide, repaglinide and acarbose.In terms of clinical superiority (lower bound of the 95%CI depicted an HbA1c reduction greater than 0.3%) alogliptin/pioglitazone and empagliflozin/linagliptin were clinically superior to 52% and 24% of the other antidiabetic medications analyzed, respectively. Alogliptin/pioglitazone was clinically superior to all DPP-4 inhibitors, colesevelam, dapagliflozin, glipizide, lixisenatide, miglitol, nataglinide, empagliflozin and pioglitazone. Empagliflozin/linagliptin was clinically superior to canagliflozin, dapagliflozin, glipizide, miglitol, nateglinide and saxagliptin.All antidiabetic agents were associated with statistically significant reductions in HbA1c relative to placebo, ranging from 0.43% for miglitol to 1.29% for glibenclamide . When coAlong with statistical significance, all therapies were found clinically superior to placebo (lower bound of the 95%CI depicted an HbA1c reduction greater than 0.3%) except for colesevelam, nateglinide and miglitol . In head-to-head comparisons, and insulin glargine was clinically superior to 40% of the other antidiabetic medications analyzed. Insulin glargine was found to be clinically superior to all DPP-4 inhibitors, colesevelam, dapagliflozin, glipizide, lixisenatide, miglitol, and nataglinide.All SGLT2 inhibitors were associated with significant weight loss when compared to placebo in the NMA (range: 2.08–2.17 kg) . When coAlogliptin/pioglitazone was associated with significant increases in BW when compared with placebo in the NMA  whereas empagliflozin/linagliptin was associated with significant weight loss . When compared to other single active agents, empagliflozin/linagliptin was associated with significant weight loss compared to all other agents except SGLT-2 inhibitors, and GLP-1 analogs. Alogliptin/pioglitazone caused significant increases in BW compared to all other active agents except SUs, repaglinide and TZDs. In terms of clinically superior weight gain, (lower bound of the 95%CI depicted a decrease in weight less than 2.3 kg), alogliptin/pioglitazone was associated with clinically superior weight gain compared to SGLT2 inhibitors, empagliflozin/linagliptin, GLP-1 analogs, and miglitol (range: 3.54–4.65 kg).The SUs, TZDs, insulin glargine and repaglinide were associated with significant increases in BW when compared with placebo in the NMA (range: 1.19–2.44 kg). GLP-1 analogs and miglitol were associated with significant weight loss (range: 1.15–2.26 kg) but there was no weight change with acarbose, any DPP-4 inhibitor, colesevelam and nateglinide when compared to placebo. When comparing active agents, GLP-1 analogs were associated with statistically greater weight loss when compared to all other agents except SGLT2 inhibitors and miglitol. While several agents exhibited statistically significant weight loss, no agent demonstrated clinically superior weight loss compared to placebo (lower bound of the 95%CI depicted a decrease in weight less than 2.3 kg). When comparing the clinical superiority of single active agents, TZDs were associated with clinically superior weight gain when compared to GLP-1 analogs (range: 3.22–4.41 kg).All SGLT2 inhibitors were associated with a decrease in SBP compared with placebo in the NMA  (range: 4.4–5.64 mmHg), and saxagliptin and sitagliptin (range: 2.26–5.79 mmHg) . No SGLTEmpagliflozin/linagliptin was associated with a decrease in SBP when compared with placebo in the NMA . In head-to-head comparisons, empagliflozin/linagliptin significantly reduced SBP when compared to SUs, linagliptin, saxagliptin and sitagliptin; however it did not show clinical superiority compared to any other active agents. There were no data to evaluate alogliptin/pioglitazone for this endpoint.Liraglutide  and sitagliptin  were associated with a decrease in SBP compared with placebo. No medication showed clinical superiority (lower bound of the 95%CIs depicted a decrease in SBP less than 5 mmHg) compared to placebo or another active agent; however, there were no data to evaluate 12 (48%) of the agents for this endpoint.Upon NMA, the SGLT2 inhibitors were not associated with an increased risk of confirmed hypoglycemia compared with placebo . In the Empagliflozin/linagliptin was not associated with increased risk of hypoglycemia compared with placebo in the NMA . In the active drug comparisons, insulin glargine, nateglinide, both meglitinides and all SUs were associated with significantly higher rates of confirmed hypoglycemia compared to empagliflozin/linagliptin . There were no data to evaluate alogliptin/pioglitazone for this endpoint.Insulin glargine, all SUs, and nateglinide were associated with significantly higher rates of confirmed hypoglycemia compared with placebo upon NMA  . All GLPNo treatment was associated with an increased risk of UTI when compared to placebo; however, there were no data to evaluate 13 (52%) of the agents for this endpoint . NMA sugResults from all pair-wise traditional meta-analyses for each of the six endpoints are reported in Results from the sensitivity analysis are reported in When HbA1c goals are not met or maintained with lifestyle modifications and metformin monotherapy, the ADA/EASD guidelines recommend patients initiate an additional antidiabetic agent from 1 of 5 classes  but do not endorse specific agents in the overall Type 2 DM population or specific patient subtypes [Our HbA1c results showed both statistical differences and clinical superiority between antidiabetic therapies. All therapies significantly reduced HbA1c, but to differing degrees when compared to placebo. Combination therapies  and insulin glargine were statistically and clinically superior in reducing HbA1c compared to a majority of other antidiabetic agents. As a class, the SGLT2 inhibitors were similar in efficacy to other non-insulin monotherapies recommended by the ADA as add-ons to metformin, which warrants an update to clinical practice guidelines to include them as a treatment option. Since the FDA uses a 0.3–0.4% noninferiority margin to assess clinical comparative efficacy, colesevelam, nateglinide and miglitol were not clinically superior to placebo  making them less attractive as adjunctive therapies .A therapy’s efficacy, or ability to lower HbA1c, must be weighed against a therapy’s propensity to cause hypoglycemia. In fact, guidelines emphasize the importance of preventing even mild hypoglycemia . InsulinThe majority of patients with Type 2 DM are overweight which may have notable impacts on insulin resistance, glycemic control and cardiovascular risk . SUs, ina priori definition of clinical superiority ; however, incoherence cannot be completely ruled out. The eight statistically significant findings resulting from 151 statistical tests are consistent with 7–8 findings that would be expected due to chance alone. We only included English-language RCTs, but due to the vast number of trials included in our meta-analysis, a limited number of trials missed for this reason would likely have minimal impact on our results. We found sparse reporting of certain endpoints (UTI and GTI) which makes it difficult to draw concrete conclusions . At the same time, our NMA cross- compared 25 therapies plus placebo on 6 different endpoints; thus multiple hypothesis testing can lead to erred conclusions of statistical differences between therapies when they do not truly exist (type 1 error). However, we conducted a sensitivity analysis using 99% CIs as a more stringent cutoff for statistical significance and found the majority of comparisons to still be statistically significant. Other agent-specific endpoints  could not be assessed due to the limited data and short follow-up periods of the included trials. Lastly, publication bias is always a concern in a meta-analysis, but we minimized this concern with our systematic search strategy, backwards citation tracking and multi-pronged grey literature searches.In persons with Type 2 DM inadequately-controlled on stable metformin monotherapy, all agents analyzed in our NMA proved effective (lowered HbA1c vs. placebo) but with differing reductions in HbA1c. Evaluated agents differed in their effects on BW, SBP, hypoglycemia and GTI; however no medication increased the risk of UTI when compared to placebo. The newest class of antidiabetic agents, the SGLT2 inhibitors, was found to provide similar HbA1c efficacy to other non-insulin monotherapies  with the added benefits of weight loss, reduced SBP and a low risk of hypoglycemia; but at a cost of an increased risk of GTI. Combination therapies resulted in some of the largest reductions in HbA1c and may be appropriate for patients requiring profound (>1%) HbA1c reductions after failing optimized metformin.S1 Checklist(DOC)Click here for additional data file.S1 Appendix(PDF)Click here for additional data file.S2 AppendixGTI = genital tract infection; HbA1c = glycated hemoglobin; IVRS = interactive voice response system; SGLT2 = sodium glucose co-transporter-2; SU = sulfonylurea; TZD = thiazolidinedione; UTI = urinary tract infection.(PDF)Click here for additional data file.S1 FigIn this figure (x) is defined as the minimally important clinical difference between two treatments (or a treatment and placebo). Using the example of HbA1c reduction, line A displays an HbA1c difference between therapies that is not statistically significant because the 95% confidence interval (CI) cross the line of no effect; lines B and C both show drug A to be statistically significantly better at lowering HbA1c than drug B, but that clinical superiority cannot be claimed in either case because the lower bound of the 95% CI crosses the (dashed) line marking the minimally important clinical difference, (MICD) x ; line D depicts a situation where drug A is both statistically significant and clinically superior in reducing HbA1c compared to drug B as evidenced by the lower bound of the 95%CI not crossing the line marking the MICD. In our network meta-analysis, the comparison of empagliflozin/linagliptin vs. dapagliflozin  would met these criteria for statistical significance and clinical superiority. MICD = minimally important clinical difference; RR = relative risk.(PDF)Click here for additional data file.S2 Fig+ = low risk of bias;? = unclear risk of bias;– = high risk of bias.(PDF)Click here for additional data file.S3 FigTherapies are reported in alphabetical order. HbA1c results are reported in WMD, % (95% CI). Results for changes in HbA1c on the top portion of the matrix represent changes in the row-defining treatment vs. those in the column-defining treatment (referent). For changes in HbA1c, negative values favor the first agent in alphabetical order. Statistically significant results are bolded. Clinically superior results are underlined. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. The results on the bottom portion of the matrix represent the reciprocal of the top portion. ACA = acarbose; ALO = alogliptin; ALO/PIO = alogliptin/pioglitazone; CANA = canagliflozin; COL = colesevelam; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = glargine; GLIB = glibenclamide; GLIC = gliclazide; GLIM = glimepiride; GLIP = glipizide; HbA1c = hemoglobin A1c; LINA = linagliptin; LIRA = liraglutide; LIX = lixisenatide; MIG = miglitol; NAT = nateglinide; PIO = pioglitazone; PLC = placebo; REP = repaglinide; ROSI = rosiglitazone; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S4 FigTherapies are reported in alphabetical order. Results are reported in WMD, kg (95% CI). Results for changes in weight on the top portion of the matrix represent changes in the row-defining treatment vs. those in the column-defining treatment (referent). For changes in weight, negative values favor the first agent in alphabetical order. Statistically significant results are bolded. Clinically superior results are underlined. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. The results on the bottom portion of the matrix represent the reciprocal of the top portion. ACA = acarbose; ALO = alogliptin; ALO/PIO = alogliptin/pioglitazone; CANA = canagliflozin; COL = colesevelam; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = glargine; GLIB = glibenclamide; GLIC = gliclazide; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; LIX = lixisenatide; MIG = miglitol; NAT = nateglinide; PIO = pioglitazone; PLC = placebo; REP = repaglinide; ROSI = rosiglitazone; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S5 FigTherapies are reported in alphabetical order. Results are reported in WMD, mmHg (95% CI). Results for changes in systolic blood pressure (SBP) on the top portion of the matrix represent changes in the row-defining treatment vs. those in the column-defining treatment (referent). For changes in SBP, negative values favor the first agent in alphabetical order. Statistically significant results are bolded. Clinically superior results are underlined. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. The results on the bottom portion of the matrix represent the reciprocal of the top portion. CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; PIO = pioglitazone; PLC = placebo; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S6 FigTherapies are reported in alphabetical order. Results for risk of confirmed hypoglycemia on the top portion of the matrix represent relative risks (RRs) of hypoglycemia in the row-defining treatment vs. those the column-defining treatment (referent). For confirmed hypoglycemia, RRs lower than 1 favor the first agent in alphabetical order. Statistically significant results are bolded. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken or the lower portion of the matrix can be used. ACA = acarbose; ALO = alogliptin; CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = glargine; GLIC = gliclazide; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; LIX = lixisenatide; NAT = nateglinide; PIO = pioglitazone; PLC = placebo; REP = repaglinide; ROSI = rosiglitazone; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S7 FigTherapies are reported in alphabetical order. Results for risk of urinary tract infection (UTI) on the top portion of the matrix represent relative risks (RRs) of UTI in the row-defining treatment vs. those the column-defining treatment (referent). For UTI, RRs lower than 1 favor the first agent in alphabetical order. Statistically significant results are bolded. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken or the lower portion of the matrix can be used. ALO/PIO = alogliptin/pioglitazone; ALO = alogliptin; CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; PIO = pioglitazone; PLC = placebo; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S8 FigTherapies are reported in alphabetical order. Results for risk of genital tract infection (GTI) on the top portion of the matrix represent relative risks (RRs) of GTI in the row-defining treatment vs. those the column-defining treatment (referent). For GTI, RRs lower than 1 favor the first agent in alphabetical order. Statistically significant results are bolded. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken or the lower portion of the matrix can be used. CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; PLC = placebo; SITA = sitagliptin.(PDF)Click here for additional data file.S9 FigTherapies are reported in alphabetical order. HbA1c results are reported in WMD, % (99% CI). Results for changes in HbA1c on the top portion of the matrix represent changes in the row-defining treatment vs. those in the column-defining treatment (referent). For changes in HbA1c, negative values favor the first agent in alphabetical order. Statistically significant results of the sensitivity analysis are colored grey. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. The results on the bottom portion of the matrix represent the reciprocal of the top portion. ACA = acarbose; ALO = alogliptin; ALO/PIO = alogliptin/pioglitazone; CANA = canagliflozin; COL = colesevelam; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = glargine; GLIB = glibenclamide; GLIC = gliclazide; GLIM = glimepiride; GLIP = glipizide; HbA1c = hemoglobin A1c; LINA = linagliptin; LIRA = liraglutide; LIX = lixisenatide; MIG = miglitol; NAT = nateglinide; PIO = pioglitazone; PLC = placebo; REP = repaglinide; ROSI = rosiglitazone; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S10 FigTherapies are reported in alphabetical order. Results are reported in WMD, kg (95% CI). Results for changes in weight on the top portion of the matrix represent changes in the row-defining treatment vs. those in the column-defining treatment (referent). For changes in weight, negative values favor the first agent in alphabetical order. Statistically significant results of the sensitivity analysis are colored grey. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. The results on the bottom portion of the matrix represent the reciprocal of the top portion. ACA = acarbose; ALO = alogliptin; ALO/PIO = alogliptin/pioglitazone; CANA = canagliflozin; COL = colesevelam; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = glargine; GLIB = glibenclamide; GLIC = gliclazide; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; LIX = lixisenatide; MIG = miglitol; NAT = nateglinide; PIO = pioglitazone; PLC = placebo; REP = repaglinide; ROSI = rosiglitazone; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S11 FigTherapies are reported in alphabetical order. Results are reported in WMD, mmHg (95% CI). Results for changes in systolic blood pressure (SBP) on the top portion of the matrix represent changes in the row-defining treatment vs. those in the column-defining treatment (referent). For changes in SBP, negative values favor the first agent in alphabetical order. Statistically significant results of the sensitivity analysis are colored grey. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. The results on the bottom portion of the matrix represent the reciprocal of the top portion. CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; PIO = pioglitazone; PLC = placebo; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S12 FigTherapies are reported in alphabetical order. Results for risk of confirmed hypoglycemia on the top portion of the matrix represent relative risks (RRs) of hypoglycemia in the row-defining treatment vs. those the column-defining treatment (referent). For confirmed hypoglycemia, RRs lower than 1 favor the first agent in alphabetical order. Statistically significant results of the sensitivity analysis are colored grey. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken or the lower portion of the matrix can be used. ACA = acarbose; ALO = alogliptin; CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = glargine; GLIC = gliclazide; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; LIX = lixisenatide; NAT = nateglinide; PIO = pioglitazone; PLC = placebo; REP = repaglinide; ROSI = rosiglitazone; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S13 FigTherapies are reported in alphabetical order. Results for risk of urinary tract infection (UTI) on the top portion of the matrix represent relative risks (RRs) of UTI in the row-defining treatment vs. those the column-defining treatment (referent). For UTI, RRs lower than 1 favor the first agent in alphabetical order. Statistically significant results of the sensitivity analysis are colored grey. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken or the lower portion of the matrix can be used. ALO/PIO = alogliptin/pioglitazone; ALO = alogliptin; CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; PIO = pioglitazone; PLC = placebo; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S14 FigTherapies are reported in alphabetical order. Results for risk of genital tract infection (GTI) on the top portion of the matrix represent relative risks (RRs) of GTI in the row-defining treatment vs. those the column-defining treatment (referent). For GTI, RRs lower than 1 favor the first agent in alphabetical order. Statistically significant results of the sensitivity analysis are colored grey. Sodium glucose co-transporter-2 (SGLT-2) inhibitors are highlighted. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken or the lower portion of the matrix can be used. CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; PLC = placebo; SITA = sitagliptin.(PDF)Click here for additional data file.S1 TableaNumber of study participants evaluated for change in A1c from baseline (sample size may vary for other endpoints). bDoses were given daily, unless otherwise specified. cData given in median (range).BID = twice daily; BMI = body mass index; DM = diabetes mellitus; FPG = fasting plasma glucose; HbA1c = hemoglobin A1c; n = number of patients; NR = not reported; OAD = oral antidiabetic drug; SBP = systolic blood pressure; SU = sulfonylurea; SE = standard error; TID = three times a day; qAM = daily AM dosing; qPM = daily PM dosing; QW = weekly. (PDF)Click here for additional data file.S2 TableaI2>50%.ACA = acarbose; ALO = alogliptin; ALO/PIO = alogliptin/pioglitazone; CANA = canagliflozin; COL = colesevelam; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = insulin glargine; GLIB = glibenclamide; GLIC = gliclazide; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; LIX = lixisenatide; MIG = miglitol; NAT = nateglinide; PIO = pioglitizone; PLC = placebo; REP = repaglinide; ROSI = rosiglitizone; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin. (PDF)Click here for additional data file.S3 TableaI2>50%.ACA = acarbose; ALO = alogliptin; ALO/PIO = alogliptin/pioglitazone; CANA = canagliflozin; COL = colesevelam; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = insulin glargine; GLIB = glibenclamide; GLIC = gliclazide; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; LIX = lixisenatide; MIG = miglitol; NAT = nateglinide; PIO = pioglitizone; PLC = placebo; REP = repaglinide; ROSI = rosiglitizone; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin. (PDF)Click here for additional data file.S4 TableaEgger’s p-value <0.05CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = insulin glargine; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; PIO = pioglitizone; PLC = placebo; SAX = saxagliptin; SBP = systolic blood pressure; SITA = sitagliptin; VILDA = vildagliptin. (PDF)Click here for additional data file.S5 TableACA = acarbose; ALO = alogliptin; CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; EXEN = exenatide; GLAR = insulin glargine; GLIC = gliclazide; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; LIRA = liraglutide; LIX = lixisenatide; NAT = nateglinide; PIO = pioglitizone; PLC = placebo; REP = repaglinide; ROSI = rosiglitizone; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S6 TableALO = alogliptin; ALO/PIO = alogliptin/pioglitazone; CANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; PIO = pioglitizone; PLC = placebo; SAX = saxagliptin; SITA = sitagliptin; VILDA = vildagliptin.(PDF)Click here for additional data file.S7 TableCANA = canagliflozin; DAPA = dapagliflozin; EMPA = empagliflozin; EMPA/LINA = empagliflozin/linagliptin; GLIM = glimepiride; GLIP = glipizide; LINA = linagliptin; PLC = placebo; SITA = sitagliptin.(PDF)Click here for additional data file.


Analysis of a skin biopsy obtained from a 42-year-old female presenting with multiple yellowish to reddish-brown nodules and plaques on the arm, chest , and abdA week later, she was diagnosed with IgG-kappa multiple myeloma .The laboratory workup showed the following: Hb: 109 g/L, Hct: 0.34 L/L, WBC: 9.5x109/L, Plt: 194x109/L, with normal differential white cell count. Other studied parameters included immunoglobulin IgG:1790 mg/dL , IgA: 279 mg/dL , IgM: 40 mg/dL ; and kappa light chains: 1830 mg/dL .The coexistence of paraproteinemias and necrobiotic xanthogranuloma is well described , and it would seem reasonable to recommend performing at least serum electrophoresis for patients affected by these rare conditions [1].Conflict of Interest StatementThe authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.


AbstractEchthronomas Forster, 1869 and two species, Echthronomasfacialis  and Echthronomasquadrinotata , are recorded for the fauna of Ukraine for the first time. Descriptions and photographs of species are provided.The genus  Echthronomas is a small genus of the subfamily Campopleginae (Hymenoptera: Ichneumonidae), represented by twelve species in the world, including four in the Western Palaearctic region , Echthronomas species, which are endoparasitoids of lepidopteran larvae, are rarely collected (c region . With thollected .Corylusavellana in beech forest (Transcarpathia) and near branches of dead Piceaabies in the mixed forest (Precarpathia). Specimens were identified using Horstmann's Fore wing 5.3 to 8.0 mm long. Body short and stout. Eye margin indented opposite antennal socket. Clypeus small, its apex convex. Mandible short. Lower tooth of mandible a little shorter than upper tooth. Temple short. Mesopleurum matt and with strong punctures. Propodeum short, with or without well defined carinae, its basal transverse carina more or less distinct, other carinae not always present. Areola and petiolar areas, when defined, broadly confluent. Propodeal spiracle circular. Tarsal claws pectinate. Areolet pointed or petiolate. First metasomal segment slender. Glymmae present. Metasoma compressed. Thyridium subcircular, separated from base of the second tergite by 0.2 to 0.6 its diameter. Ovipositor as long as apical depth of metasoma. This genus is distinguished from other Campoplegine genera by combination of the following characters Fig. .Type status:Other material. Occurrence: recordedBy: Varga A.; sex: 1 female; Location: country: Ukraine; stateProvince: Ivano-Frankivsk region, Bogorodchany district, Mochary; verbatimLocality: 5 km NE of Bogorodchany; verbatimElevation: 300–350 m; verbatimLatitude: 48° 50' N; verbatimLongitude: 24° 35' E; Event: eventDate: 19 July 2011Type status:Other material. Occurrence: recordedBy: Varga A.; sex: female; Location: country: Ukraine; stateProvince: Ivano-Frankivsk region, Bogorodchany district, Mochary; verbatimLocality: 5 km NE to Bogorodchany; verbatimElevation: 300-350 m; verbatimLatitude: 48° 50' N; verbatimLongitude: 24° 35' E; Event: eventDate: 10 June 2012Female. This species is easily distinguishable from all Echthronomas species in having a punctate propodeum, without traces of carinae, yellow frons (inner margins of eyes), face, clypeus, mandibles, malar space Type status:Other material. Occurrence: recordedBy: Varga A.; sex: female; Location: country: Ukraine; stateProvince: Transcarpathian region, Rakhiv district, Kvasy; verbatimElevation: 630-650 m; verbatimLatitude: 48° 08' N; verbatimLongitude: 24° 16' E; Event: eventDate: 16 August 2009Female. This species is easily distinguishable from all Echthronomas species in having a transversely wrinkled propodeum, black clypeus with two yellow lateral spots, black face and malar space  differs from Echthronomasquadrinotata  in having entirely yellow fore and mid coxae, clypeus, and malar space, partly yellow face, and a black metasoma with only red apically tergites II–IV. Another species, Echthronomasochrostoma , is similar to Echthronomasquadrinotata , but differs in having a yellow malar space and clypeus   .Eilema sp. (Arctiidae) (ctiidae) .


Scientific Reports6: Article number: 20272;10.1038/srep20272 published online: 02012016; updated: 03302016This Article contains errors in Affiliation 3. The correct affiliation is listed below:Center for Nanotechnology Innovation @NEST, Istituto Italiano di Tecnologia, Piazza San Silvestro 12-56127 Pisa, Italy.


At the last follow-up (fifty-one months), the patient was showing very-long term antiviral response, progressive decline of secondary immune activation and absence of significant side-effects. Further research is required to fully verify the real impact on therapeutic choice/regimen.Hepatitis C virus (HCV) has been recognized to be both a hepato- and lymphotropic virus. HCV lymphotropism represents an essential detail in the pathogenesis of virus-related autoimmune and lymphoproliferative disorders, ranging from clonal expansion of B-cells with organ and non-organ-specific autoantibody production up to overt non-Hodgkin’s lymphoma along a continuous step-by-step model of B-cell lymphomagenesis, where the intermediated mixed cryoglobulinemia could be considered as a stage of suppressible antigen-driven lymphoproliferation. The HCV long-lasting extrahepatic replicative state generates an abnormal systemic immunological response, including rheumatoid factor (RF) and cryo- and non-cryoprecipitable immune complexes, as well as clinical manifestations, comprising dermatitis, polyarthralgias and arthritis, pulmonary disease, aplastic anemia, glomerulonephritis and vasculitis. The mechanism of these extra-hepatic disorders is thought of as linked to immune complex disease, but their pathogenesis is poorly clarified. Immune-suppressive treatment could induce high-level hepatitis C viremia and impair hepatic disease. We report a female patient, whose chronic HCV-related liver cirrhosis with associated explosive, but oligosymptomatic lymphoproliferative immune response,  Interaction between Hepatitis C virus (HCV) and the immune system represents a well-known pathogenic mechanism that causes liver and extrahepatic damage in chronically infected patients. Several reports in the literature have confirmed that HCV infection leads to different types of immune disease such as cryoglobulinemia, rheumatoid arthritis, Sjogren’s syndrome, hemolytic anaemia and severe thrombocytopenia, autoimmune hepatitis, thyroid disorders and diabetes mellitus. These manifestations, labelled as autoimmune diseases, are reckoned to be caused by the lymphotropism of the virus: particularly, the interaction between the E2 glycoprotein of the HCV envelope and the CD81 receptor, expressed by hepatocytes and B lymphocytes, could play a fundamental role. Chronically infected lymphocytes constitute a reservoir of virus, but on the other hand persistent infection of lymphoid tissue induces a chronic stimulation of the immune system based on various molecular mechanisms, of which the activation of Bcl-2, a proto-oncogene that prolongs lymphocytes survival, and induces a switch of T lymphocytes both in Th2 phenotype and Th1 phenotype, plays a key role. The Th2 phenotype increases humoral immunity and production of autoantibodies, while the Th1 phenotype causes mixed cryoglobulinemia (MC) and immune disorders affecting various organs . In 2012i.e., cytomegalovirus, Epstein-Barr virus and herpes simplex virus and autoimmunity (ANA/AMA/anti LKM as well as serum anti-gliadin and anti-endomysium) were negative. Hemocromocytometric analysis showed moderate anemia  and low platelets count . The patient presented with abnormal levels of laboratory parameters, suggesting the presence of cytolysis and cholestasis, i.e., AST 265 U/L , ALT 241 U/L (nv < 35), ALP 108 U/L (nv < 104), gammaGT 67 U/L (nv < 36), direct bilirubin 0.42 mg/dL (nv < 0.3) LDH 468 U/L (nv < 450), as well as of impaired liver synthesis; she showed hypo-albuminemia  and typical alterations of coagulation suggesting a subacute-chronic disseminated intravascular coagulopathy (DIC) (PT INR: 1.49 (nv < 1.3), anti-thrombin III: 44.7% (nv 70%–120%), d-dimerus: >6500 μg/L (nv < 198), fibrinogen degradation products (FDP): 20–40 (nv < 10). Markers of liver proliferation were raised , tissue polypeptide specific antigen, TPS: 6717 ng/mL (nv < 80)). Imaging features (US and CT of abdomen) evidenced slight increase of the liver volume (mainly at level of the right lobe), hypertrophy of the caudate and left lobes, irregular edges, coarse pattern, splenomegaly  and ascites. Gastroscopy evidenced signs of portal hypertension (congestive gastropathy). The ascitic episode was resolved after three weeks by infusion of plasma-expanders  and combined diuretic therapy (furosemide 40 mg i.v. 3 times/week + potassium kanreonate 200 mg/day per os). Moreover, a marked immune activation represented by the following data was noted: typization of cryoprecipitate: IgM-k, II type, mixed-, mono- and poly-clonal; cryocrit: 40%, RF: 53,200 UI/mL , monoclonal component IgM: 0.61 g/dL, k type, IgM total: 37.6 g/L (nv 0.4–2.3), IgG total: 25.9 g/L (nv 7–16), circulating immune complexes (CIC) C1q: 86 mcg/mL (nv < 40), CIC C3d: 62 mcg/mL (nv < 24), anti-cardiolipine antibodies: 40.5 U/mL (nv < 20) and beta2-microglobulin: 5203 ng/mL (nv < 2740) . Medical history revealed anti-HCV antibodies, which were documented from 1991, and a dysmetabolic phenotype characterized by visceral obesity, HDL cholesterol reduction, impaired fasting glucose and arterial hypertension controlled by drug therapy; laboratory parameters and imaging features evidenced initial organ damage . Therefore, she was admitted to our ward and was provided with a full clinical laboratory and instrumental evaluation. The virological markers of HCV infection showed infection by HCV, 1b genotype, moderate plasmatic levels of HCV-RNA  and C/T polymorphism of IL 28B gene promoter. Markers of other hepatotropic viruses,  < 2740) . The eryOn January 2005, the patient started only pegylated IFN alfa 2b 1.5 mcg/kg/week. The choice was due to both reduced Hb levels and Glomerular Filtration Rate (GFR), detected during routine check-ups in the course of diuretic therapy, adding Ribavirin (RBV) after six months only.The aim of AT was the suppression of the viral antigenic driver and the reduction of virus-related immune stimulation.On May 2005 : The patient manifested a transitory purpuric rash on legs that spontaneously resolved after 10–14 days. Recurrence of rash was not observed. Slight dyschromia, which was in accordance with a histological pattern of “mixed cytoclastic dermatitis”, persisted.On June 2005 (the sixth month of AT): The patient continued the administration of pegylated IFN alfa 1.5 mcg/kg/week and received a 800 mg-dose of RBV, with Hb and GFR levels ameliorated.10), improvement of anaemia  and of platelets count  and other laboratory liver tests.Peripheral oedemas and ascites resolved. Immune modulating and/or cyto-reductive therapies such as rituximab/corticosteroids at high dosage/cyclophosphamide/plasmapheresis were considered as alternatives in case of failure, but they were not thought to be necessary. Of interest, only in this period did the patient reach the greatest peak of RF 58,200 UI/mL  and cryocrit (60%); at same time the first and unique episode of consumption of complement was observed: C4: 0.081 g/L (nv 0.1–0.4). IgM: 23.8 g/L  a. Moreovk monoclonal component (MC): 0.58 g/dL, beta2-microglobulin: 4700 ng/mL (nv < 2740), first normalization of liver cytolysis and residual plasmatic levels of virus (8700 UI/mL with a reduction of two log10)) (On March 2006 (the 15th month of therapy and the ninth month of RBV combined therapy) the patient showed reduction of immune activation parameters , cryocrit: 35%, IgM: 18.8 g/L (nv 0.4–2.3), IgM- log10)) a; howevek MC: 0.58 g/dL, beta2-microglobulin: 4730 ng/mL (nv < 2740); again, normalization of liver cytolysis and reduction of plasmatic levels of virus were confirmed ; moreover, sentinel superficial lymph nodes disappeared and the patient had the opportunity to continue AT.On September 2006  a further reduction of immune activity was observed, RF: 30,000 UI/mL , cryocrit: 32%, IgM: 15.3 g/L (nv 0.4–2.3), IgM-k MC: 0.74 g/dL, beta2-microglobulin: 4890 ng/mL (nv < 2740), (10) persisted. In addition to the resolution of sentinel superficial lymphadenopathy, the patient experienced a regression of deep abdominal lymph nodes, while isolated enlarged lymph nodes at the hepatic hylus persisted ; however, during this period a moderate intolerance to AT occurred and a reduction of therapeutic dosage was needed; therefore, the patient switched to pegylated-IFN alfa 2b, 1 mcg/kg/week, and RBV, 600 mg/day.Between March 2007 (the 27th month of therapy and the 21st month of combination with RBV) and September 2007 (the 33rd of therapy and the 27th month of combination with RBV): A further reduction of immune activation was observed , cryocrit: 30%, IgM: 9.7 g/L (nv 0.4–2.3), IgM-< 2740), a; both nk MC: 0.62 g/dL, beta2-microglobulin: 4420 ng/mL (nv < 2740)), the patient experienced first virological remission and viral plasma levels were undetectable using PCR Real Time.On March 2008 —the 12th month of reduced dosage: In association with reduced immune activation and confirmed normalization of liver cytolysis , cryocrit: 27%, IgM: 5.7 g/L (nv 0.4–2.3), IgM-k MC: 0.57 g/dL, beta2-microglobulin: 3620 ng/mL (nv < 2740), absent HCV viremia ),  and March 2010  the patient was showing normal laboratory liver tests and improved immunological and virological parmameters: (RF: 4300 UI/mL (nv ≤ 15), cryocrit: 20%, IgM-lTime)), . VirologEnd Therapy Response), RF: 2780 UI/mL (nv ≤ 15), cryocrit: 19%, IgM-k MC: 0.54 g/dL, beta2-microglobulin: 3120 ng/mL (nv < 2740) (On June 2010 (the 66th month of therapy and the 60th month of combination with RBV—the 39th month of reduced dosage and three months after the switch to 0.75 mcg/Kg/week and 400 mg/day of RBV)—27 months after first virological remission, the patient ended AT. Main laboratory examinations confirmed both virological/immunological remission and normalization of liver tests: absent plasma viral levels  indicating  < 2740) . Only muOf particular note, ultrasonographic examination revealed axillary and inguinal lymph nodes exhibiting tapered shapes and a hyperhecoic hylus .very Long-Term Response; a minimal immune activity—RF: 1560 UI/mL , cryocrit: 12% , IgM: 5.07 g/L (nv 0.4–2.3), CIC C1Q: 71 μg/mL (nv 0–40), CIC C3d: 116 μg/mL (nv 0–24), IgM-k MC: 0.77 g/dL, beta2-microglobulin: 3115 ng/mL (nv < 2740),   translocation and a possible evolution to a centro-follicular lymphoma.Between June 2010 and October 2014 the patient underwent a prolonged and well-documented follow-up that confirmed both normal laboratory liver parameters—AST: 19 U/L (nv < 35), ALT: 15 U/L (nv < 35), total proteins: 8.0 g/dL (nv 6.5–8.2), albumin: 4.5 g/dL, total cholesterol: 187 mg/dL, LDH: 403 U/L (nv < 450), AFP: 1.8 ng/mL (nv < 15), TPS: 75 ng/mL (nv < 80) and virological remission with absent plasma levels of virus at 51st month of follow-up indicating a < 2740), b. The anTable 2a) Laboratory parameters during the antiviral therapy; (b) Laboratory parameters during the follow-up.; patients with SVR had no relapse of NHLs and responders were characterized by longer survival time without disease [The patient presented with a dysregulated IgM gammopathy showing humoral (RF) and cryoprecipitate (mixed cryoglobulinemia of type II) activity induced by an amplified HCV replication. Gammopathy could be not classified as Waldenstrom macroglobulinemia or nodular lymphoid hyperplasia (NLH), which is a lymphoproliferative disease with small cells due to a possible lymphoplasmacytic/lymphoplasmacitoid immunocytoma. These observations are in accordance with previously mentioned studies, which revealed a higher incidence of immune stimulation and lymphocytosis in HCV patients; particularly, infection can be an antigenic trigger of lymphocytic stimulation and persist for several years before NLH occurrence. Therefore, lymphocytic stimulation can be considered an important factor to predict evolution to lymphoma ,5. Of malymphoma . The Herlymphoma . On the lymphoma . Moreovelymphoma . Similar disease . AT repr disease . In low- disease ,16; consi.e., combined AT and evaluation of the long-term prognosis. Thus, in these patients we suggest that physicians carefully evaluate some markers of immune activation, such as cryoglobulins, RF, fractions of complement, circulating immunocomplexes, presence of mono-clonal gammopathy or poly-clonal hypergammaglobulinemia and typical symptoms of MC. In fact, these parameters could indicate an urgent necessity to consolidate therapy, obviously in selected patients, in order to eradicate the latent infection of B-lymphocytes and reduce both the incidence of MC/NHL and relapse of liver disease. As a final observation, the content of this case report prompts a revision of the optimal timing of the newly appearing direct-acting, IFN-free antiviral combinations.AT was an efficient approach in our patient affected by HCV-related liver cirrhosis, improving laboratory parameters. A fundamental element of HCV chronic infection is the abnormal immune response against viral antigens that frequently leads to a permanent chronic immune reaction. Although this response, well modulated, is central to the virus eradication, the same response could cause liver damage and provoke a dysregulated immune activation leading to severe clinical manifestations, such as MC or NHLs. Particularly, chronic lymphocytic proliferation and hypergammaglobulinemia in some conditions evolve to lymphoproliferative syndromes, which could manifest without severe symptoms, at least at an initial stage. Therefore, in addition with evaluation of laboratory liver tests, immune activation needs careful consideration to decide an optimal and safe therapeutic strategy, At the last follow-up (fifty one months), the patient was showing very-long term antiviral response, progressive decline of secondary immune activation and absence of significant side-effects. Further research is required to fully verify the true impact of therapeutic choice/regimen in similar cases.


Data from the SINGLE trial demonstrated that 88% of treatment-naive HIV-1 patients treated with dolutegravir and abacavir/lamivudine (DTG+ABC/3TC) achieved viral suppression at 48 weeks compared with 81% of patients treated with efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC). It is unclear how this difference in short-term efficacy impacts long-term cost-effectiveness of these regimens. This study sought to evaluate the long-term cost-effectiveness of DTG+ABC/3TC versus EFV/TDF/FTC from a US payer perspective.An individual discrete-event simulation model tracked the disease status and treatment pathway of HIV-1 patients. The model simulated treatment over a lifetime horizon by tracking change in patients’ CD4 count, occurrence of clinical events , treatment switch and death. The model included up to four lines of treatment. Baseline patient characteristics, efficacy and safety of DTG+ABC/3TC and EFV/TDF/FTC were informed by data from the SINGLE trial. The efficacy of subsequent lines of treatment, clinical event risks, mortality, cost and utility inputs were based on literature and expert opinion. Outcomes were lifetime medical costs, quality-adjusted life-years (QALYs) (both discounted at 3% per annum) and the incremental cost-effectiveness ratio (ICER).Compared with EFV/TDF/FTC, DTG+ABC/3TC increased lifetime costs by $58,188 and per-person survival by 0.12 QALYs, resulting in an ICER of $482,717/QALY. In sensitivity analyses testing conservative assumptions about EFV/TDF/FTC's efficacy beyond the trial period, ICERs comparing DTG+ABC/3TC to EFV/TDF/FTC remained high . In a scenario in which the price of EFV/TDF/FTC was reduced by 10% to reflect the potential for price reduction as EFV goes off patent, DTG+ABC/3TC's ICER compared to EFV/TDF/FTC was $600,916/QALY. When DTG+ABC/3TC's price was reduced by 10%, the resulting ICER comparing DTG+ABC/3TC to EFV/TDF/FTC was $302,171/QALY.Compared with EFV/TDF/FTC, DTG+ABC/3TC resulted in substantially higher cost, slightly better QALY over lifetime, and ICERs far exceeding standard cost-effectiveness thresholds, indicating that the incremental benefit in efficacy associated with DTG+ABC/3TC may not be worth the incremental increase in costs.


There is an error in affiliation #1. The correct affiliation #1 should be: Lipid and Atherosclerosis Unit. IMIBIC/Reina Sofia University Hospital/University of Cordoba, Cordoba, Spain and CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain


Cell & Bioscience.Three research groups led by Dr. Robert Clarke of Georgetown University Medical Center, Washington, DC, USA; Dr. Lixin Wei of Shanghai Jiaotong University, Shanghai, China; and Dr. Zhiming Zhang of Xiamen University, Xiamen, Fujian, China, won the 2014 Ming K Jeang Award for Excellence in  Cell & Bioscience in 2014, have been selected to receive the Ming K Jeang Award for Excellence in Cell & Bioscience. The Ming K Jeang Award for Excellence in Cell & Bioscience was established in 2011 with a generous donation from the Ming K. Jeang Foundation to honor outstanding research articles published in Cell & Bioscience, the official journal of the Society of Chinese Bioscientists in America . A committee of Cell & Bioscience Editors, chaired by Dr. Dong-Yan Jin, considered all research articles published in the journal in 2014 to select the following three articles to receive the award [Mitochondria directly donate their membrane to form autophagosomes during a novel mechanism of parkin-associated mitophagyCell & Bioscience 2014, 4:16 (27 March 2014)Katherine L Cook, David R Soto-Pantoja, Mones Abu-Asab, Pamela AG Clarke, David D Roberts, Robert Clarke Abstract | Full text | PDF | ePUB | PubMed | Cited on BioMed CentralAutophagy protects against palmitate-induced apoptosis in hepatocytesCell & Bioscience 2014, 4:28 (21 May 2014)Ning Cai, Xue Zhao, Yingying Jing, Kai Sun, Shufan Jiao, Xiaojing Chen, Haozheng Yang, Yan Zhou, Lixin Wei Abstract | Full text | PDF | ePUB | PubMedMicroRNA-20b promotes cell growth of breast cancer cells partly via targeting phosphatase and tensin homologue (PTEN)Cell & Bioscience 2014, 4:62 (14 October 2014)Weidong Zhou, Guixiu Shi, Qiuyan Zhang, Qiuwan Wu, Boan Li, Zhiming Zhang Abstract | Full text | PDF | ePUB | PubMedWe are very pleased to announce that three research groups, who each published an outstanding research article in he award :MitochonCongratulations to these three groups of investigators for jobs well done!We are looking forward to receiving contributions of outstanding research articles from the scientific community in 2015 and beyond.


AbstractSaxatilomyspaulinae Musser et al., 2005 was first discovered by Paulina's Limestone Rat Saxatilomyspaulinae in Quang Binh province. This is the first record of Saxatilomyspaulinae in Vietnam. External and craniodental characteristics of all specimens clearly exhibit the characters of Saxatilomyspaulinae as described in Saxatilomyspaulinae in Vietnam is characterized by complicated terrain comprising low karst towers (around 400 m) with steep slopes covered under limestone humid evergreen forest. The forest has been affected by selected timber logging in the past, but still has a complex 4-layer structure. The population of Saxatilomyspaulinae in Vietnam is threatened by rodent trapping/snaring and habitat disturbance. More status surveys should be conducted to assess the species distributional range and its population status for undertaking relevant conservation measures.In April 2014, we conducted a rodent survey and collected four (4) whole specimens of  Laonastesaenigmamus . Baits were made of fresh manioc or sweet potato. All captured animals were anesthetized and measured for external measurements following Saxatilomyspaulinae) were preserved in 70% ethanol for later identification using museum mammal collections. Species identification follows Those individuals that could not be identified to the species level in the field ; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 315 m; verbatimLatitude: 17°48’N; verbatimLongitude: 105°55’E; Event: eventDate: April 14, 2014; habitat: Karst forest; Record Level: collectionID: NXN-217; institutionCode: IEBR; collectionCode: DVZ-Rodentia; ownerInstitutionCode: IEBRType status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: female; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 315 m; verbatimLatitude: 17°48’N; verbatimLongitude: 105°55’E; Event: eventDate: April 15, 2014; habitat: Karst forest; Record Level: collectionID: NXN-218; institutionCode: IEBR; collectionCode: DVZ-Rodentia; ownerInstitutionCode: IEBRType status:Other material. Occurrence: recordedBy: Nghia Xuan Nguyen; individualCount: 1; sex: male; Location: country: Vietnam; stateProvince: Quang Binh; verbatimLocality: Thuong Hoa Commune, Minh Hoa District; verbatimElevation: 298 m; verbatimLatitude: 17°48’N; verbatimLongitude: 105°55’E; Event: eventDate: April 17, 2014; habitat: Karst forest; Record Level: collectionID: NXN-221; institutionCode: IEBR; collectionCode: DVZ-Rodentia; ownerInstitutionCode: IEBRSaxatilomyspaulinae  were collected in April 2014. The external and craniodental measurements of these specimens are shown in Table Saxatilomyspaulinae described in Four whole specimens of Saxatilomyspaulinae were captured only in Thung Uc locality  of Thuong Hoa Commune , at elevation of 295 - 315 m, under limestone humid evergreen forest  with steep slopes covered under limestone humid evergreen forest. The slopes have many large limestone boulders and crevices. The forest on the slopes has been affected by selected timber logging in the past; however, a 3-4 layer forest structure remains, with the following characters:Pometiapinnata (Sapindaceae), Dracontomelonduperreanum (Anacardiaceae), Toonasurenii (Meliaceae), Paviesiaanamensis (Sapindaceae), Pterospermumgrewiaefolium (Sterculiaceae), Mahuca sp., Hopea sp., Streblusasper (Moraceae), Litsea sp. (Lauraceae), Sumbaviopsismacrophylla (Euphorbiaceae), Actinodaphne sp. (Lauraceae), Pometiachinensis (Sapindaceae), Choerospondiasaxillaris (Anacardiaceae), Alangiumridleyi (Alangiaceae), Knema sp. (Myristicaceae), etc.The canopy tree layer consists of trees 20-30 m high with stem diameter 0.5-0.8 m. The most common trees species are: Knemacorticosa (Myristicaceae), Streblustonkinensis, Streblusasper (Moraceae), Xylopiavielana (Annonaceae), Diospyros sp. (Ebenaceae), Caryotamitis (Arecaceae), Arengapinnata (Arecaceae), Camelia sp. (Theaceae), Actinodaphne sp. (Lauraceae), Pterospermum sp. (Sterculiaceae), Litsea sp. (Lauraceae), Ormosialaoensis (Fabaceae), Nepheliumlappaceum (Sapindaceae), Sumbaviopsismacrophylla (Euphorbiaceae), Paranepheliumspirei (Sapindaceae), Alangiumridleyi (Alangiaceae), Baccaurea sp. (Euphorbiaceae), Aglaia sp. (Meliaceae), etc.The middle tree layer consists of trees 10-15 m high with stem diameter 0.3-0.5 m. The most common species are Euphorbiaceae, Theaceae, Myrtaceae and Verbenaceae. Some dominant species are Antidesma sp. (Euphorbiaceae), Trevesiapanmalta , Litseavaliabilis (Lauraceae), Arengapinnata (Arecaceae), Excoecariacochinchinensis (Euphorbiaceae), as well as seedlings of trees from higher layers.The scrub layer consists of trees 3-7 m high, mostly with twisted stems, many branches, and several stems rising from one base. The most common species are from the families Araceae, the genera Calamus and Caryota (family Arecaceae), and many herb species from families Urticaceae, Melastomataceae, Balsaminaceae, Poaceae, Begoniaceae, Podipoliaceae, Convallariaceae, Zingiberaceae, Urticaceae and Acanthaceae. Some of the most common species are Homalomenaocculta (Araceae), Aglaonemasimplex (Araceae), Aglaonemasiamensis (Araceae), Taccachantrieri (Taccaceae), Aspidistratypica , Piper sp. (Piperaceae), Corymborkisveratrifolia (Orchidaceae), etc.The herb and fern layer is about 0.5-3 m high, with trees of 0.2-3 m high from family Saxatilomyspaulinae, several other ground-living rodent species are found in this habitat including Bandicotaindica, Berylmysbowersi, Leopoldamyssabanus, Leopoldamysedwardsi, Maxomysmoi, Maxomyssurifer, Niviventerfulvescens, Niviventerlangbianis, Niviventertenaster, Rattustanezumi, Rattusandamanensis, and Laonastesaenigmamus (Apart from nigmamus .Saxatilomyspaulinae in Quang Binh province (Vietnam) is wildlife hunting and habitat disturbance. The distribution area of the Saxatilomyspaulinae is situated close to the villages of ethnic minorities . These minority groups are very poor and their livelihood much depends on wildlife and forest products. Wildlife hunting is a long tradition of the local people, and a practice that remains extensive currently. Most men 15 to 60 years in age in these villages are engaged in wildlife hunting. Their hunting season lasts about eight months per year (from July to February). The most widely used mean for trapping rodents is metal spring snares. Each hunter usually keeps 30-100 active snares in forests; some hunters keep up to 300-500 active snares. Unfortunatlely, we were not able to estimate how many individuals of Saxatilomyspaulinae they capture each year.Main threats to the population of Simple comparison of external and craniodental measurement of specimens from Vietnam with those of specimens from Lao indicates that specimens from Vietnam are generally larger than specimens from Lao Table . HoweveSaxatilomyspaulinae was reported to inhabit steep rocky slopes with large limestone boulders covered in heavily degraded deciduous forest mixed with scrub and bamboo at the base of the surrounding massive karst , while trapping and habitat disturbance remain as current threats to the species survival. More surveys need to be conducted to assess the species distributional range and the status of its populations for undertaking relevant conservation measures.Before this study, e of Lao . Our recSaxatilomyspaulinae and Laonastesaenigmamus share the same limestone forest habitat in Central Indochina Limestone. The Laonastesaenigmamus is the only surviving member of the otherwise extinct rodent family Diatomyidae, that was formerly believed to have been extinct for more than 11 million years (It is interesting that both on years . Both sp


Adalimumab (ADA) is approved for use in moderate to severe juvenile idiopathic arthritis (JIA) in patients (pts) ≥4 years (yrs) old in the US, EU, and Japan. Limited data are available in pts <4 yrs old.To assess the safety and effectiveness of >1 year of ADA therapy in pts aged 2 to <4 yrs old or ≥4 yrs old weighing <15 kg with moderately to severely active polyarticular JIA2 (maximum = 20 mg/dose) every other week (wk) +/- methotrexate for a minimum of 24 wks in an ongoing international, multicenter, open-label, phase 3b study until achieving the limit for age (≥4 yrs) and weight (≥15 kg). Adverse events (aes) were summarized for all visits up to 96 wks. Clinical effectiveness endpoints were assessed as observed, and included American College of Rheumatology pediatric (pedacr) 30/50/70/90 responses through wk 60, and JIA outcome parameters .JIA pts were treated with ADA 24 mg/m32 pts were randomized; through wk 60, two pts withdrew due to aes (JIA worsening or flare) and 2 withdrew for other reasons. AE incidence rates included: any aes 91%), serious aes (16%), infectious aes (78%), and serious infections (9%). No deaths, malignancies, or opportunistic infections were reported. 90% of pts had achieved pedacr30 at wk 60 (Table %, seriouIn this very young population with polyarticular JIA, primary clinical trial data revealed that the safety profile and effectiveness of ADA were comparable to that observed in older children with JIA. Moreover, ADA had no adverse impact on height or weight, as data reflected improvement in growth metrics through wk 60 of the study.D. Kingsbury Grant/Research Support from: abbvie Inc., P. Quartier Grant/Research Support from: abbvie, Novartis, Chugai-Roche and Pfizer, Consultant for: abbvie, Novartis, Chugai-Roche and Pfizer, V. Arora Shareholder of: abbvie Inc., Employee of: abbvie Inc., J. Kalabic Shareholder of: abbvie Inc., Employee of: abbvie Inc., H. Kupper Shareholder of: abbvie Inc., Employee of: abbvie Inc., N. Mozaffarian Employee of: Former employee of abbvie Inc.


Ulinastatin is a protease inhibitor derived from human urine with strong anti-inflammatory and anticoagulant activity . BesidesAKI, acute kidney injury; CPB, cardiopulmonary bypass; MAP, mean arterial pressure; RRT, renal replacement therapy; SCr, serum creatinine


While pleural effusion and ascites secondary to acute pancreatitis are common, clinically relevant pericardial effusion and cardiac tamponade are observed rarely. In a study by Pezzilli et al., pleural effusion was noted in 7 of the 21 patients with acute pancreatitis whereas the authors detected pericardial effusion development in only three. The authors asserted that pleural effusion was associated with severe acute pancreatitis, while pericardial effusion and the severity of acute pancreatitis were not significantly related. Pleural effusion and ascites develop frequently in acute severe pancreatitis, while pericardial effusion does rarely , 2. In pA 44-year-old female presented with cough, phlegm, nasal discharge and fever. A week later, she developed abdominal pain radiating to the back, chest pain and shortness of breath, therefore admitted for inpatient care. Her history included asthma and diabetes mellitus. Her familial history involved no relevant findings. The findings on physical examination were as follows: arterial blood pressure: 110/70 mm Hg, heart rate per minute: 102, fever: 38,2°C, oxygen saturation: 93% and tachypnea. Cardiac sounds were coming deeply and pericardial friction rubs were heard. Respiratory sounds were coarse bilaterally. Widespread abdominal tenderness was remarkable. Examinations of other systems yielded normal results. With laboratory analyses: leukocyte: 17,5 x109 /L, neutrophil: 41%, lymphcoyte: 53%, Hct: 36%, platelet: 359 x109 /L, CRP: 209 mg/L, amylase: 1552 IU/L, lipase: 1238 IU/L, AST: 24 IU/L, ALT: 28 IU/L, ALP: 68 IU/L, GGT: 28 IU/L, LDH: 232 IU/L, total bilirubin: 0,8µmol/L, conjugated bilirubin: 0,4µmol/L, glucose: 123 mg/dL, creatinine: 0,5 mg/dL. Other biochemical tests yielded normal results. Electrocardiogram demonstrated sinus tachycardia and reduction in voltage. Chest X-ray on admission showed a massive enlargement of the cardiac silhouette without pleural effusions ,C,D). PeThe mechanism of pericardial effusion in acute pancreatitis has not been elucidated completely but a number of theories have been suggested, including chemical pericarditis due to pancreatic enzymes carried by lymphatic vessels or available in the circulation, necrosis of vascular walls in fatty areas, necrosis of the subpericardial fat and fistulous connection between abdominal and pericardial cavities . MediastIn conclusion pericardial effusion secondary to acute pancreatitis may develop via several mechanisms. Acute pancreatitis secondary to viral infection and pericardial effusion development should also be considered in the differential diagnosis. Complete resolution is usually achieved with symptomatic treatment in acute pancreatitis except for pericardial effusion associated with fistula presence.


The correct title is: Renal Function Outcomes and Risk Factors for Stage 3B Chronic Kidney Disease after Urinary Diversion in Patients with Muscle Invasive Bladder Cancer. The correct citation is: Hatakeyama S, Koie T, Narita T, Hosogoe S, Yamamoto H, Tobisawa Y, et al. (2016) Renal Function Outcomes and Risk Factors for Stage 3B Chronic Kidney Disease after Urinary Diversion in Patients with Muscle Invasive Bladder Cancer. PLoS ONE 11(2): e0149544. doi:There are formatting errors in