Objective To evaluate sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes at varying cardiovascular and renal risk. Design Network meta-analysis. Data sources Medline, Embase, and Cochrane CENTRAL up to 11 August 2020. Eligibility criteria for selecting studies Randomised controlled trials comparing SGLT-2 inhibitors or GLP-1 receptor agonists with placebo, standard care, or other glucose lowering treatment in adults with type 2 diabetes with follow up of 24 weeks or longer. Studies were screened independently by two reviewers for eligibility, extracted data, and assessed risk of bias. Main outcome measures Frequentist random effects network meta-analysis was carried out and GRADE (grading of recommendations assessment, development, and evaluation) used to assess evidence certainty. Results included estimated absolute effects of treatment per 1000 patients treated for five years for patients at very low risk (no cardiovascular risk factors), low risk (three or more cardiovascular risk factors), moderate risk (cardiovascular disease), high risk (chronic kidney disease), and very high risk (cardiovascular disease and kidney disease). A guideline panel provided oversight of the systematic review. Results 764 trials including 421 346 patients proved eligible. All results refer to the addition of SGLT-2 inhibitors and GLP-1 receptor agonists to existing diabetes treatment. Both classes of drugs lowered all cause mortality, cardiovascular mortality, non-fatal myocardial infarction, and kidney failure (high certainty evidence). Notable differences were found between the two agents: SGLT-2 inhibitors reduced mortality and admission to hospital for heart failure more than GLP-1 receptor agonists, and GLP-1 receptor agonists reduced non-fatal stroke more than SGLT-2 inhibitors (which appeared to have no effect). SGLT-2 inhibitors caused genital infection (high certainty), whereas GLP-1 receptor agonists might cause severe gastrointestinal events (low certainty). Low certainty evidence suggested that SGLT-2 inhibitors and GLP-1 receptor agonists might lower body weight. Little or no evidence was found for the effect of SGLT-2 inhibitors or GLP-1 receptor agonists on limb amputation, blindness, eye disease, neuropathic pain, or health related quality of life. The absolute benefits of these drugs vary substantially across patients from low to very high risk of cardiovascular and renal outcomes (eg, SGLT-2 inhibitors resulted in 5 to 48 fewer deaths in 1000 patients over five years; see interactive decision support tool ( https://magicevidence.org/match-it/200820dist/#!/ ) for all outcomes. Conclusions In patients with type 2 diabetes, SGLT-2 inhibitors and GLP-1 receptor agonists reduced cardiovascular and renal outcomes, with notable differences in benefits and harms. Absolute benefits are determined by individual risk profiles of patients, with clear implications for clinical practice, as reflected in the BMJ Rapid Recommendations directly informed by this systematic review. Systematic review registration PROSPERO CRD42019153180.

IMPORTANCE Numerous glucose-lowering drugs are used to treat type 2 diabetes. OBJECTIVE To estimate the relative efficacy and safety associated with glucose-lowering drugs including insulin. DATA SOURCES Cochrane Library Central Register of Controlled Trials, MEDLINE, and EMBASE databases through March 21, 2016. STUDY SELECTION Randomized clinical trials of 24 weeks' or longer duration. DATA EXTRACTION AND SYNTHESIS Random-effects network meta-analysis. MAIN OUTCOMES AND MEASURES The primary outcome was cardiovascular mortality. Secondary outcomes included all-cause mortality, serious adverse events, myocardial infarction, stroke, hemoglobin A 1c (HbA 1C) level, treatment failure (rescue treatment or lack of efficacy), hypoglycemia, and body weight. RESULTS A total of 301 clinical trials (1 417 367 patient-months) were included; 177 trials (56 598 patients) of drugs given as monotherapy; 109 trials (53 030 patients) of drugs added to metformin (dual therapy); and 29 trials (10 598 patients) of drugs added to metformin and sulfonylurea (triple therapy). There were no significant differences in associations between any drug class as monotherapy, dual therapy, or triple therapy with odds of cardiovascular or all-cause mortality. Compared with metformin, sulfonylurea (standardized mean difference [SMD], 0.18 [95% CI, 0.01 to 0.34]), thiazolidinedione (SMD, 0.16 [95% CI, 0.00 to 0.31]), DPP-4 inhibitor (SMD, 0.33 [95% CI, 0.13 to 0.52]), and α-glucosidase inhibitor (SMD, 0.35 [95% CI, 0.12 to 0.58]) monotherapy were associated with higher HbA 1C levels. Sulfonylurea (odds ratio [OR], 3.13 [95% CI, 2.39 to 4.12]; risk difference [RD], 10% [95% CI, 7% to 13%]) and basal insulin (OR, 17.9 [95% CI, 1.97 to 162]; RD, 10% [95% CI, 0.08% to 20%]) were associated with greatest odds of hypoglycemia. When added to metformin, drugs were associated with similar HbA 1C levels, while SGLT-2 inhibitors offered the lowest odds of hypoglycemia (OR, 0.12 [95% CI, 0.08 to 0.18]; RD, −22% [−27% to −18%]). When added to metformin and sulfonylurea, GLP-1 receptor agonists were associated with the lowest odds of hypoglycemia (OR, 0.60 [95% CI, 0.39 to 0.94]; RD, −10% [95% CI, −18% to −2%]). CONCLUSIONS AND RELEVANCE Among adults with type 2 diabetes, there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA 1C levels compared with any other drug classes. All drugs were estimated to be effective when added to metformin. These findings are consistent with American Diabetes Association recommendations for using metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.

Telemedicine, the use of telecommunications to deliver health services, expertise and information, is a promising but unproven tool for im proving the quality of diabetes care. We summarized the effectiveness of differ ent methods of telemedicine for the management of diabetes compared with usual care. METHODS:We searched MEDLINE, Em base and the Cochrane Central Register of Controlled Trials databases (to Novem ber 2015) and reference lists of existing systematic reviews for randomized con trolled trials (RCTs) comparing telemedi cine with usual care for adults with diabe tes. Two independent reviewers selected the studies and assessed risk of bias in the studies. The primary outcome was glycated hemoglobin (HbA 1C ) reported at 3 time points (≤ 3 mo, 4-12 mo and > 12 mo). Other outcomes were quality of life, mortality and episodes of hypoglyce mia. Trials were pooled using random effects metaanalysis, and heterogeneity was quantified using the I 2 statistic. RESULTS:From 3688 citations, we identi fied 111 eligible RCTs (n = 23 648). Tele medicine achieved significant but modest reductions in HbA 1C in all 3 followup peri ods (difference in mean at ≤ 3 mo: −0.57%, 95% confidence interval [CI] −0.74% to −0.40% [39 trials]; at 4-12 mo: −0.28%, 95% CI −0.37% to −0.20% [87 trials]; and at > 12 mo: −0.26%, 95% CI −0.46% to −0.06% [5 trials]). Quantified heterogene ity (I 2 statistic) was 75%, 69% and 58%, re spectively. In metaregression analyses, the effect of telemedicine on HbA 1C ap peared greatest in trials with higher HbA 1C concentrations at baseline, in trials where providers used Web portals or text mes saging to communicate with patients and in trials where telemedicine facilitated medication adjustment. Telemedicine had no convincing effect on quality of life, mortality or hypoglycemia. INTERPRETATION:Compared with usual care, the addition of telemedicine, espe cially systems that allowed medication adjustments with or without text mes saging or a Web portal, improved HbA 1C but not other clinically relevant out comes among patients with diabetes. RESEARCH E342CMAJ | MARCH 6, 2017 | VOLUME 189 | ISSUE 9tional clinical trials have recently been published, which suggests the value of an updated review. We did a systematic review and quantitative synthesis of randomized controlled trials (RCTs) com paring the impact of different methods of telemedicine with usual care on glycated hemoglobin (HbA 1C ) and healthrelated quality of life in people with diabetes mellitus. MethodsWe performed a systematic review of RCTs that compared telemedi cine with usual care for the management of diabetes (type 1 and type 2). The review was reported according to an accepted guide line. 32 We followed a written but unregistered protocol. We included studies if they were RCTs (parallel, cluster or cross over); were published in English; enrolled adult patients with diabe tes; compared telemedicine (some electronic form of providerto patient communication) with usual care; and reported the degree of metabolic control measured ...

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Successful severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires proteolytic cleavage of the viral spike protein. While the role of the host transmembrane protease serine 2 in SARS-CoV-2 infection is widely recognized, the involvement of other proteases capable of facilitating SARS-CoV-2 entry remains incompletely explored. Here, we show that multiple members from the membrane-type matrix metalloproteinase (MT-MMP) and a disintegrin and metalloproteinase families can mediate SARS-CoV-2 entry. Inhibition of MT-MMPs significantly reduces SARS-CoV-2 replication in vitro and in vivo. Mechanistically, we show that MT-MMPs can cleave SARS-CoV-2 spike and angiotensin-converting enzyme 2 and facilitate spike-mediated fusion. We further demonstrate that Omicron BA.1 has an increased efficiency on MT-MMP usage, while an altered efficiency on transmembrane serine protease usage for virus entry compared with that of ancestral SARS-CoV-2. These results reveal additional protease determinants for SARS-CoV-2 infection and enhance our understanding on the biology of coronavirus entry.

A series of β-cyclodextrin derivatives were designed and synthesized. The derivatives were investigated as functional monomers in molecularly imprinted polymeric solid-phase microextraction (MIP-SPME) fiber coatings. The coatings, with a layer thickness of 250 μm, were immobilized onto stainless steel using a capillary tube as a mold. This study employed a simple, easy, and reproducible method to prepare uniform coatings for polychlorophenols extraction. The combination of molecular inclusion effects and the molecular imprinting sites was expected to enhance the molecular recognition ability for polychlorophenols. Compared with non-imprinted polymer coatings and MIP coatings with methacrylic acid as the functional monomer, the β-cyclodextrin MIP-SPME coatings exhibited significantly higher extraction amounts and excellent selectivity to the template of triclosan. The MIP-SPME coatings exhibited a favorable synergistic extraction capacity resulting from the β-cyclodextrin cavity and molecularly imprinted binding sites. The method of β-cyclodextrin MIP-SPME coupled with high performance liquid chromatography (HPLC) for triclosan and polychlorophenols analysis in real water samples was developed. The limit of quantification was 1 μg/L for the three polychlorophenols. The recovery for three analytes ranged from 83.71% to 109.98%, with the relative standard deviation (RSD) of 2.83% to 12.19%. The β-cyclodextrin MIP-SPME fiber coatings could be used for at least 100 cycles. Graphical Abstract Synergistic effects in β-cyclodextrin MIP-SPME.

Genetic engineering (GE) technology is widely used in plant modification. However, the results of modification may not exactly meet the expectations. Herein, we propose a new multi-omics method for GE plant evaluation based on the optimized use of the metID algorithm. Using this method, we found that flavonoid accumulation was at the expense of the great sacrifice of Lphenylalanine in GE tomatoes for the first time. Meanwhile, the ceramide series of sphingolipid is synthesized de novo from L-serine, and ceramides are the primary source of vesicles coated with flavonoids and secreted from the endoplasmic reticulum. Therefore, the accumulation of the ceramide series of sphingolipid changed the cell component of intracellular organelles. Furthermore, the improvement of the method allows us to identify more metabolites related to dysregulated pathways.