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Objective: To quantify the effectiveness and safety of intra-articular interventions for knee and hip osteoarthritis (OA) through a systematic review and Bayesian random-effects network meta-analysis., Design: We searched CENTRAL and regulatory agency websites (inception-2023) for large, English-language, randomized controlled trials (RCTs) (≥100 patients/group) examining any intra-articular intervention., Primary Outcome: pain intensity., Secondary Outcomes: physical function and safety outcomes. Pain and function outcomes were analyzed at 2, 6, 12, 24, and 52 weeks post-randomization, and presented as standardized mean differences (SMDs) (95% credible intervals, 95% CrI). The prespecified minimal clinically important between-group difference (MID) was -0.37 SMD. Safety outcomes were presented as odds ratios (OR) (95% CrI)., Findings: Among 57 RCTs (22,795 participants) examining 18 intra-articular interventions, usual care or placebo, treatment effects were larger in 35 high-risk-of-bias trials than in 22 low/unclear-risk-of-bias trials. In the main analysis (excluding high-risk-of-bias trials), triamcinolone had the highest probabilities of reaching the MID at weeks 2 and 6 (75.3% and 90%, respectively) with corresponding SMDs of -0.48 (95% CrI,-0.85 to -0.10) and -0.53 (95% CrI,-0.79 to -0.27) compared to placebo (1 trial). The complex homeopathic products Tr14/Ze14 showed therapeutic potential at week 6 compared to placebo (SMD:-0.42, 95% CrI,-0.71 to -0.11, 63.5% probability of reaching the MID, 1 trial). Hyaluronic acid had no effect on pain (SMD:-0.04, 95% CrI,-0.19 to 0.11, 11 trials) but a higher risk of dropouts due to adverse events (OR: 2.01, 95% CrI,1.08 to 3.77) and serious adverse events (OR: 1.86, 95% CrI, 1.16 to 3.03) than placebo., Conclusion: Triamcinolone had the highest probabilities to have a treatment effect beyond the MID at weeks 2-6. Large RCTs with lower risk of bias indicate that the effects of 16 intra-articular interventions in knee or hip OA were smaller than the MID, and that most were consistent with placebo effects. Lack of evidence of long-term effectiveness underscores the need for further research beyond 24 weeks., Competing Interests: Declaration of Competing Interest Peter Tugwell is an advisory committee member of the Canadian Reformulary Group Inc., a company that reviews evidence for health insurance companies' employer drug plans. He is also the unpaid Chair of the Management Group of OMERACT, a registered non-profit independent medical research organization dedicated to improving health outcomes for patients with musculoskeletal conditions. OMERACT receives arms-length funding from 11 companies (AbbVie, AstraZeneca, Aurinia, BMS, Centrexion, GSK, Horizon Pharma Inc., Janssen, Novartis, Pfizer, and Sparrow). The remaining authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Electrocatalysis holds the key to the decentralized production of hydrogen peroxide via the two-electron oxygen reduction reaction (ORR, O 2(g) +2H + +2e - ->H 2 O 2(aq) ). However, cost-effective, active, and selective catalysts are still sought after. While density functional theory (DFT) has already led to the discovery of various enhanced catalysts, it has a severe yet often unnoticed drawback: the ill description of O 2 and H 2 O 2 . Here, we analyze the impact of the errors in those two species on the most widespread activity plots in the literature, namely free-energy diagrams and Sabatier-type volcano plots. Uncorrected or partially corrected gas-phase energies lead to appreciably different activity plots that may provide inaccurate predictions. Indeed, we show for a variety of electrocatalysts that only when the errors in O 2 and H 2 O 2 are corrected can DFT mimic the experiments. In sum, this work provides concrete guidelines to avoid a common pitfall of computational models for electrocatalytic hydrogen peroxide production., (© 2024 The Authors. ChemSusChem published by Wiley-VCH GmbH.)

Background: Routine screening for viral infections at blood donation is important to avoid transfusion-transmitted infections. It also offers an opportunity to detect an asymptomatic infection., Objective: To study changes in serology positivity for viral infections (B and C hepatitis, HTLV-1/2, and HIV) at blood donation in a blood bank from Southern Brazil, comparing two periods of 5 years: the period from 2013 to 2017 with the period from 2018 to 2022. In addition, data on the donor fidelity rate during the studied period were sought., Methods: Retrospective study using data from 2013 to 2022 from a single blood center electronic database from Curitiba, Southern Brazil., Results: A significant drop in positive serology for all studied viruses was observed: highest in HIV (OR=0.39; 95% CI=0.27-0.57) and lowest in total anti HBc (0.56; 95 CI=0.50-0.63). Anti HBc serology became more commonly seen in women in the period of 2018-2022 when compared to men. No changes in the distribution of positive serology according to donors' ages were observed. Loyalty rates had a median of 70%, with the lowest being 60% in 2013, while the highest was 73% in 2018 and 2022., Conclusion: A significant reduction in discarded blood bags due to viral serology was observed when the period of 2013-2017 was compared to 2018-2022 on this blood bank; the highest reduction was observed in HIV serology and the lowest in HBc serology, which became more common in women in the second period. High rates of donor fidelity were observed during the period studied.

The catalytic performance of modified hydroxyapatite nanoparticles, Ca 10-x Fe x-y W y (PO 4 ) 6 (OH) 2 , was applied for the degradation of methylene blue (MB), fast green FCF (FG) and norfloxacin (NOR). XPS analysis pointed to the successful partial replacement of Ca by Fe. Under photo-electro-Fenton process, the catalyst Ca 4 Fe II 1·92 W 0·08 Fe III 4 (PO 4 ) 6 (OH) 2 was combined with UVC radiation and electrogenerated H 2 O 2 in a Printex L6 carbon-based gas diffusion electrode. The application of only 10 mA cm -2 resulted in 100% discoloration of MB and FG dyes in 50 min of treatment at pH 2.5, 7.0 and 9.0. The proposed treatment mechanism yielded maximum TOC removal of ∼80% and high mineralization current efficiency of ∼64%. Complete degradation of NOR was obtained in 40 min, and high mineralization of ∼86% was recorded after 240 min of treatment. Responses obtained from LC-ESI-MS/MS are in line with the theoretical Fukui indices and the ECOSAR data. The study enabled us to predict the main degradation route and the acute and chronic toxicity of the by-products formed during the contaminants degradation., Competing Interests: Declaration of competing interest The authors have participated in all step of manuscript, since design, analysis up to interpretation of the data. Have no conflict of interest. In addition, this manuscript has not been submitted to, nor is under review at, another journal or other publishing similar., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Psoriatic arthritis (PA) is a chronic inflammatory systemic arthritis that can result in loss of functional capacity and joint deformation. This systematic review assessed the effectiveness and safety of biological and target synthetic drugs for treating PA., Methods: We searched for randomized clinical trials (RCTs) that evaluated the use of Adalimumab, Etanercept, Infliximab, Golimumab, Secukinumab, Certolizumab Pegol and Tofacitinib in the main general databases and clinical trial registers databases. The primary outcomes were ACR 50, PsARC, and serious adverse events. Two independent reviewers performed study selection and data extraction. Network meta-analyses were conducted using a random effects model and frequentist approach. The CINeMA software was used to assess the certainty of evidence., Results: We included 33 RCTs (n = 11,034). The results from the network meta-analysis for the ACR 50 at 6-months follow-up showed that all drugs were superior to placebo, with Secukinumab (high certainty of evidence), Infliximab (very low certainty of evidence) and Adalimumab (high certainty of evidence) ranking the highest. Regarding the PsARC (at 6-months follow-up), all drugs, except for Golimumab (very low certainty of evidence), were superior to placebo, with Etanercept (low certainty of evidence), Infliximab (low certainty of evidence) and Certolizumab Pegol (low certainty of evidence) being the most effective drugs. There were no significant differences in the risk of serious adverse events between the drugs and placebo. Golimumab (very low certainty of evidence), Secukinumab (low certainty of evidence), and Adalimumab (very low certainty of evidence) ranked the highest for safety., Conclusions: In conclusion, based on the balance between efficacy and safety, Secukinumab and Adalimumab may be the preferred options among the evaluated drugs for treating patients with PsA. However, caution is necessary when interpreting the safety findings, as they are supported by evidence of low to very low certainty. Consequently, the balance between benefits and potential risks may change as new safety evaluation studies become available., Protocol Registration: PROSPERO: CRD42022315577., (© 2024. The Author(s).)

What is the impact of switching between biologics and biosimilars of adalimumab, etanercept, and infliximab on efficacy and safety for rheumatoid arthritis? A systematic review and network meta-analysis were performed to compare switching and non-switching groups of treatments. Pooled Risk Relative (RR) or standardised mean differences (SMD) with 95% credible intervals (95% CrIs) were obtained. Seventeen randomized trials with a switching phase involving 6,562 patients were included. Results showed that a single switch from biologics to biosimilars compared to continuing biologics had comparable effects for primary and co-primary outcomes, the American College of Rheumatology criteria with 20% response (ACR20) (7 trials, 1,926 patients, RR 0.98, 95% CrIs 0.93 to 1.03) and the Health Assessment Questionnaire-Disability Index (HAQ-DI) (5 trials, 1,609 patients, SMD - 0.07, 95% CrIs - 0.23 to 0.1), and within the equivalence margins: ACR20 [RR 0.94, 1.06] and HAQ-DI [SMD - 0.22, 0.22]. The risk of treatment-emergent adverse events, discontinuation, and positive anti-drug antibodies were comparable after switching. Safety results were imprecise, and the follow-up period might not be sufficient to evaluate long-term effects, especially malignancies. Overall, the practice of single switching between approved biologics and biosimilars of Tumour Necrosis Factor inhibitors is efficacious and safe for rheumatoid arthritis., (© 2023. Springer Nature Limited.)

Importance: Biosimilar drugs are potentially lower-cost versions of biologics that may improve access to therapy. However, there is a lack of adequate systematic reviews demonstrating equivalence between these drugs for the treatment of rheumatoid arthritis (RA)., Objectives: To assess the efficacy, safety, and immunogenicity associated with biosimilars of adalimumab, etanercept, and infliximab compared with their reference biologics in patients with RA., Data Sources: MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and LILACS databases were searched from inception to September 2021., Study Selection: Head-to-head randomized clinical trials (RCTs) of biosimilars of adalimumab, etanercept, and infliximab and their biologic reference drugs for RA were assessed., Data Extraction and Synthesis: Two authors independently abstracted all data. Meta-analysis was conducted with bayesian random effects using relative risks (RRs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes, with 95% credible intervals (CrIs) and trial sequential analysis. Specific domains were assessed for the risk of bias in equivalence and noninferiority trials. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline., Main Outcomes and Measures: Equivalence was tested using prespecified margins for the American College of Rheumatology criteria, with at least 20% improvement in the core set measures (ACR20) (ie, RR, 0.94 to 1.06), and for the Health Assessment Questionnaire-Disability Index (HAQ-DI) (ie, SMD, -0.22 to 0.22). Secondary outcomes included 14 items measuring safety and immunogenicity., Results: A total of 25 head-to-head trials provided data on 10 642 randomized patients with moderate to severe RA. Biosimilars met equivalence with reference biologics in terms of ACR20 response (24 RCTs with 10 259 patients; RR, 1.01; 95% CrI, 0.98 to 1.04; τ2 = 0.000) and change of HAQ-DI scores (14 RCTs with 5579 patients; SMD, -0.04; 95% CrI, -0.11 to 0.02; τ2 = 0.002) considering prespecified margins of equivalence. Trial sequential analysis found evidence for equivalence for ACR20 since 2017 and HAQ-DI since 2016. Overall, biosimilars were associated with similar safety and immunogenicity profiles compared with reference biologics., Conclusion and Relevance: In this systematic review and meta-analysis, biosimilars of adalimumab, infliximab, and etanercept were associated with clinically equivalent treatment effects compared with their reference biologics for the treatment of RA.

Background: There is widespread agreement amongst clinicians that people with non-specific low back pain (NSLBP) comprise a heterogeneous group and that their management should be individually tailored. One treatment known by its tailored design is the McKenzie method (e.g. an individualized program of exercises based on clinical clues observed during assessment)., Objectives: To evaluate the effectiveness of the McKenzie method in people with (sub)acute non-specific low back pain., Search Methods: We searched CENTRAL, MEDLINE, Embase and two trials registers up to 15 August 2022., Selection Criteria: We included randomized controlled trials (RCTs) investigating the effectiveness of the McKenzie method in adults with (sub)acute (less than 12 weeks) NSLBP., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: This review included five RCTs with a total of 563 participants recruited from primary or tertiary care. Three trials were conducted in the USA, one in Australia, and one in Scotland. Three trials received financial support from non-commercial funders and two did not provide information on funding sources. All trials were at high risk of performance and detection bias. None of the included trials measured adverse events. McKenzie method versus minimal intervention (educational booklet; McKenzie method as a supplement to other intervention - main comparison) There is low-certainty evidence that the McKenzie method may result in a slight reduction in pain in the short term (MD -7.3, 95% CI -12.0 to -2.56; 2 trials, 377 participants) but not in the intermediate term (MD -5.0, 95% CI -14.3 to 4.3; 1 trial, 180 participants). There is low-certainty evidence that the McKenzie method may not reduce disability in the short term (MD -2.5, 95% CI -7.5 to 2.0; 2 trials, 328 participants) nor in the intermediate term (MD -0.9, 95% CI -7.3 to 5.6; 1 trial, 180 participants). McKenzie method versus manual therapy There is low-certainty evidence that the McKenzie method may not reduce pain in the short term (MD -8.7, 95% CI -27.4 to 10.0; 3 trials, 298 participants) and may result in a slight increase in pain in the intermediate term (MD 7.0, 95% CI 0.7 to 13.3; 1 trial, 235 participants). There is low-certainty evidence that the McKenzie method may not reduce disability in the short term (MD -5.0, 95% CI -15.0 to 5.0; 3 trials, 298 participants) nor in the intermediate term (MD 4.3, 95% CI -0.7 to 9.3; 1 trial, 235 participants). McKenzie method versus other interventions (massage and advice) There is very low-certainty evidence that the McKenzie method may not reduce disability in the short term (MD 4.0, 95% CI -15.4 to 23.4; 1 trial, 30 participants) nor in the intermediate term (MD 10.0, 95% CI -8.9 to 28.9; 1 trial, 30 participants)., Authors' Conclusions: Based on low- to very low-certainty evidence, the treatment effects for pain and disability found in our review were not clinically important. Thus, we can conclude that the McKenzie method is not an effective treatment for (sub)acute NSLBP., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Chemical epigenetic manipulation of Botrytis cinerea strain B05.10 with the histone deacetylase inhibitor SAHA led to the isolation of a new cryptic metabolite, botrycinereic acid (22a). This compound was also overproduced by inactivating the stc2 gene, which encodes an unknown sesquiterpene cyclase. Its structure and absolute configuration were determined by extensive spectroscopic NMR and HRESIMS studies, and electronic circular dichroism calculations. Its biosynthesis was studied by feeding 2 H and 13 C isotopically labeled precursors to B. cinerea Δstc2 mutant. A detailed analysis of the labeling and coupling patterns into botrycinereic acid (22a) revealed that this compound derives from l-phenylalanine and l-leucine., (Copyright © 2022 Elsevier Inc. All rights reserved.)

A key step in the biosynthesis of numerous polyketides is the stereospecific formation of a spiroacetal (spiroketal). We report here that spiroacetal formation in the biosynthesis of the macrocyclic polyketides ossamycin and oligomycin involves catalysis by a novel spiroacetal cyclase. OssO from the ossamycin biosynthetic gene cluster (BGC) is homologous to OlmO, the product of an unannotated gene from the oligomycin BGC. The deletion of olmO abolished oligomycin production and led to the isolation of oligomycin-like metabolites lacking the spiroacetal structure. Purified OlmO catalyzed complete conversion of the major metabolite into oligomycin C. Crystal structures of OssO and OlmO reveal an unusual 10-strand β-barrel. Three conserved polar residues are clustered together in the β-barrel cavity, and site-specific mutation of any of these residues either abolished or substantially diminished OlmO activity, supporting a role for general acid/general base catalysis in spiroacetal formation.

Postpartum uterine infections of dairy cows promote a local and systemic inflammation and interfere with reproductive efficiency. The aim of this study was to evaluate the effect of steroid hormones including progesterone (P4) and estradiol (E2) on the systemic inflammatory response of cows after being challenged with an intrauterine infusion of lipopolysaccharide (LPS). For this, a hemogram and serum dosage of haptoglobin (Hp) in eight primiparous Gir cows ovariectomized were performed on day (day 0) and after 24 h (day +1). Four cows (n = 4) were challenged (day 0) with 20 mL of 0.9% NaCl + 12.5 μg/kg LPS, and four cows (n = 4) were challenged (day 0) with 20 mL of 0.9% NaCl. For this, the study was divided in four experimental groups as: (1) Control group: without any hormonal treatment before day 0; (2) Group 24 h - E2: 1 mg of estradiol benzoate 24 h before (day -1); (3) Group 24 h - P4: 2.0 g of P4 device 24 h before (day -1); (4) Group 14 d - P4: 2.0 g of P4 device 14 days before (day -14). In the systemic response to LPS, there was an increase in Hp (control group; 24 h - P4 group; 14 d - P4 group), and on day +1 the Hp of 14 d - P4 group was higher when compared to the other groups. On day 0, the 14 d - P4 group had an increase in circulating leukocytes and lymphocytes cells than the control group (P < 0.01). On day +1 after LPS-challenge the 14 d - P4 group showed a decrease in circulating lymphocytes, eosinophils, and monocytes (P < 0.05). A neutrophilia with left shift in the two treatments with P4 (day +1), in addition to a thrombocytopenia and lower platelets compared to the 24 h - E2 group (P < 0.05) (day 0) were recorded. It was concluded that ovariectomized cows challenged with LPS, previously submitted to steroid hormones induce a systemic inflammatory response. Also, the systemic response is more intense after previous prolonged exposure to P4 and less intense after exposure to E2. This study provided important information relating the effect of ovarian steroids on the systemic inflammatory response of cows challenged with intrauterine LPS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Bis(2-ethylhexyl) phthalate (DEHP) has been widely used for the production of plastics, and the compound has also been found to act as endocrine disruptor. Exposure to DEHP has been found to cause several hormonal problems, including decreased fertility. Due to the environmental and health risks posed by the use of DEHP, the present study employed molecular docking, molecular dynamics, and free energy analyses (MM-GBSA, MM-PBSA, and SIE) aiming at evaluating the action of DEHP and that of two other compounds (ATEC and DL9TH), tested as potential DEHP substitutes, on two hormone receptors (sex hormone-binding globulin - SHBG - and progesterone receptor - PR). The results obtained showed that ATEC may be a good substitute for DEHP in the production of plastics, such as PVC, considering that the compound recorded the greatest free energy values with respect to binding with SHBG (-31.36 kcal/mol obtained from MM-GBSA; -20.28 kcal/mol for MM-PBSA, and -7.40 for SIE) and PR (-36.40 kcal/mol for MM-GBSA; -27.00 kcal/mol for MM-PBSA, and -8.51 kcal/mol for SIE) - this shows that ATEC presented the least activity in the two hormone receptors. The findings of this study provide relevant insights on potential substitutes for DEHP and help shed light on the action of these new efficient substances, which have similar properties to DEHP (ATEC and DL9TH) yet do not act as endocrine disruptors.Communicated by Ramaswamy H. Sarma.

Introduction: Mini health technology assessment (HTA) reports have been used to support policy makers and health systems by providing a timely summary of scientific evidence. The objective of this meta-epidemiologic study was to evaluate the quality of reporting of mini-HTA reports published in Brazil., Methods: An electronic search for all mini-HTA reports published between 2014 and March 2019 was conducted in the SISREBRATS and CONITEC databases. The study selection and data extraction were performed by two independent assessors. The following data were extracted: bibliographic data; research question; characteristics of the population, health technologies and outcomes assessed; eligibility criteria; information about searches and study selection; risk of bias assessment; quality of evidence assessment; synthesis of results; and recommendation about the technology evaluated. A descriptive analysis was used to summarize the information retrieved from all the included mini-HTA reports., Results: We included 103 mini-HTA reports, the great majority of which (92.3 percent) focused on the coverage of the technologies in the healthcare system, with more than 60 percent being about drugs. Only five mini-HTA reports (4.8 percent) gave reasons for the choice of outcomes, and fifteen (14.5 percent) discriminated between primary and secondary outcomes. All mini-HTAs reported the databases searched and 99 percent of them reported using Medline. Sixty percent of the mini-HTA reported assessing the risk of bias, and 52 percent reported assessing the quality of evidence., Conclusion: The quality of reporting of the mini-HTA reports performed in Brazil is insufficient and needs to be improved to guarantee transparency and replicability.

Objective: To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose., Design: Systematic review and network meta-analysis of randomised trials., Data Sources: Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021., Eligibility Criteria for Selecting Studies: Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis., Outcomes and Measures: The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed., Review Methods: Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo., Results: 192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%)., Conclusions: Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis., Systematic Review Registration: PROSPERO number CRD42020213656., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Arthritis Society, Canada Research Chairs Programme, National Institute for Health Research, Chevening Scholarship Program for the submitted work. PJ serves as unpaid member of the steering group of trials funded by Appili Therapeutics, Abbot Vascular, and Terumo; he has received research grants to the institution from Appili Therapeutics, and honorariums to the institution for participation in advisory boards or consulting from Amgen, Ava and Fresenius, but has not received personal payments by any pharmaceutical company or device manufacturer. AJS has been a paid consultant by Janssen-Cilag and GlaxoSmithKline. PT has received royalty payments as contributing author and editor for journals, textbooks and articles published by Elsevier, Little Brown, Wolters Kluwer, and John Wiley and Sons; PT has been an independent paid consultant to CHEOR Solutions (Canada), Innovative Science Solutions LLC and Reformulary Group; he serves as unpaid chair of the management subcommittee, of the executive committee of OMERACT; OMERACT receives unrestricted educational grants from the American College of Rheumatology, European League of Rheumatology, Amgen, Astra Zeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Genzyme/Sanofi, Horizon Pharma, Merck, Novartis, Pfizer, PPD, Quintiles, Regeneron, Savient, Takeda Pharmaceutical, UCB Group, Vertex, Forest and Bioiberica; PT serves as an independent committee member in Data Safety Monitoring Boards of FDA approved trials being conducted by UCB Biopharma GmbH and SPRL, Parexel International and Prahealth Sciences. All other authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. All authors report no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Biologic drugs such as adalimumab, etanercept, and infliximab represent major first-line and second-line treatments for rheumatoid arthritis (RA) patients. However, their high cost poses a massive burden on healthcare systems worldwide. The expiration of patents for these biologics has driven the production of biosimilar drugs, which are potentially less costly and remarkably similar, albeit not identical to the reference molecules. This paper aims to outline the protocol of a systematic review that will investigate the efficacy and safety profile of biosimilars compared to biologics (objective 1) and the impact of switching between biosimilar drugs and reference biologics on the management of RA patients (objective 2)., Methods: We will investigate the effects of any biosimilars of adalimumab, etanercept, and infliximab on RA patients. We will include randomized controlled trials (RCTs) or quasi-RCTs to assess efficacy and safety outcomes and RCTs with two- or multiple-part designs to evaluate the consequences of switching from reference biologics to biosimilar drugs (and vice-versa). Electronic searches will be performed through MEDLINE (via PubMed), EMBASE, LILACS, and CENTRAL (from inception to April 2021). Two independent reviewers will screen studies, extract data, and evaluate the risk of bias. The latter will be carried out considering specific domains from equivalence trials and switching studies. Random-effects models will be fitted to obtain summary estimates using either relative risk or standardized mean difference as a metric. The primary outcome will be the rate of treatment success according to the American College of Rheumatology 20 (ACR20), and the co-primary outcome will be the Health Assessment Questionnaire-Disability Index (HAQ-DI). Conclusions will be based on equivalence hypothesis testing using predefined margins of equivalence elicited from a group of experienced rheumatologists and prior studies. The overall certainty of the evidence will be assessed based on the GRADE system., Discussion: The present investigation proposes a comprehensive, clinician-oriented approach to assess the equivalence and the impact of switching between biosimilars and biologics on the management of patients with RA. Our results will elucidate the efficacy, safety, immunogenicity of biosimilars, and the clinical consequences of substituting biologics with biosimilars in the management of RA., Systematic Review Registration: PROSPERO CRD42019137152 and CRD42019137155., (© 2021. The Author(s).)

Propolis is a honeybee product with various biological activities, including antidiabetic effects. We previously reported that artepillin C, a prenylated cinnamic acid derivative isolated from Brazilian green propolis, acts as a peroxisome proliferator-activated receptor γ (PPARγ) ligand and promotes adipocyte differentiation. In this study, we examined the effect of baccharin, another major component of Brazilian green propolis, on adipocyte differentiation. The treatment of mouse 3T3-L1 preadipocytes with baccharin resulted in increased lipid accumulation, cellular triglyceride levels, glycerol-3-phosphate dehydrogenase activity, and glucose uptake. The mRNA expression levels of PPARγ and its target genes were also increased by baccharin treatment. Furthermore, baccharin enhanced PPARγ-dependent luciferase activity, suggesting that baccharin promotes adipocyte differentiation via PPARγ activation. In diabetic ob/ob mice, intraperitoneal administration of 50 mg/kg baccharin significantly improved blood glucose levels. Our results suggest that baccharin has a hypoglycemic effect on glucose metabolic disorders, such as type 2 diabetes mellitus.

Bacterial vaginosis (BV) has been considered as dysbiosis state whose etiology is not fully understood. This condition affects a large number of women of reproductive age and its study has been highly relevant due to the growing association of BV with and gynecological and obstetric complications and diseases, in addition to a greater susceptibility to sexually transmitted diseases, including HIV. The vaginal microbiota composition presents high variability among different ethnic groups of women, although, generally, the prevalence of lactobacilli species has been reported. Several studies suggest they may play a protective role, especially Lactobacillus crispatus whose population is typically present in low proportions in women with BV. This review article describes the contributions and limitations of genomic approaches in elucidating protective characteristics and mechanisms associated with colonization and persistence of lactobacilli strains. Although some genetic features were associated with resilience of L. crispatus during BV, furher studies are required to uncover their functions.

Cutaneous leishmaniasis (CL) is a neglected tropical disease (NTD), endemic mainly in low-income countries that lack adequate basic health care. The emergence of resistant parasites to pentavalent antimonials has led to the search for new treatments for CL. Photodynamic therapy (PDT) is a promising non-invasive and less toxic alternative for the treatment of CL. The present work describes the synthesis, characterization and photodynamic effect against CL of a new metalloporphyrin Pd (II) meso-tetra[4-(2-(3-n-pentadecylphenoxy)ethoxy]phenylporphyrin (PdP) derived from the cashew nut shell liquid (CNSL). The PdP complex presented a singlet oxygen quantum yield of 0.49, favoring a type II photochemical reaction. The results of the photodynamic experiment carried out with PdP on the promastigote forms of Leishmania braziliensis indicated a mortality percentage of 70 % of the cells when compared to the control after exposure to blue light (λ = 420 nm). Besides this, the metalloporphyrin PdP did not show considerable toxicity to macrophages, indicating the cell viability of the compound. Therefore, this metalloporphyrin derived from biomass represents an interesting alternative as a potential therapeutic drug for the treatment of CL through PDT, especially for patients with intolerance to the chemotherapeutic drugs currently available., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Natural products have been universally approached in the research of novel trends useful to detail the essential paths of the life sciences and as a strategy for pharmacotherapeutics., Objective: This work focuses on further modification to the 6-hydroxy-flavanone building block aiming to obtain improved BCR-ABL kinase inhibitors., Methods: Ether derivatives were obtained from Williamson synthesis and triazole from Microwave- assisted click reaction. Chemical structures were finely characterized through IR, 1H and 13C NMR and HRMS. They were tested for their inhibitory activity against BCR-ABL kinase., Results: Two inhibitors bearing a triazole ring as a pharmacophoric bridge demonstrated the strongest kinase inhibition at IC50 value of 364 nM (compound 3j) and 275 nM (compound 3k)., Conclusion: 6-hydroxy-flavanone skeleton can be considered as a promising core for BCR-ABL kinase inhibitors., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The p-coumaric acid is a phenolic compound present in large quantities in the extract of Baccharis dracunculifolia DC, a Brazilian medicinal plant used to treat gastric ulcer. Given the necessity for finding new chemical components capable of accelerating gastric healing, in this study, the effects of the p-coumaric acid were evaluated in the acetic acid-induced ulcer model in rats, where histological, inflammatory, and oxidative parameters were analyzed. The healing property was also evaluated in the scratch assay on fibroblast cells (L929) and the cytotoxicity of p-coumaric acid was assessed in both L929 and human gastric adenocarcinoma (AGS) cells by MTT assay. The treatment with p-coumaric acid (10 mg/kg, p.o.) for 7 days, twice a day, decreased by 44.6% the acetic acid-induced gastric ulcer compared with the vehicle-treated group. The vehicle control-treated group showed a larger extension of the ulcer base and an extensive damage into the mucosa and submucosa layers, which were mitigated by the treatment with p-coumaric acid. This beneficial effect was also associated with increased levels of mucin and reduced glutathione, decreased amount of lipid hydroperoxides, and increased superoxide dismutase and catalase activities without interfering with the activity of myeloperoxidase in the gastric tissue. The compound promoted the restructuring of the cell monolayer in the scratch test and did not show toxicity in the L929 cell line, while reduced the viability of the AGS, a lineage of human gastric adenocarcinoma. Thus, p-coumaric acid may be considered a natural source for the treatment of gastric ulcers, by reinforcing protective factors of gastric mucosa and by accelerating gastric healing.

The bacterial strain PO100/5 was isolated from a skin abscess taken from a pig (Sus scrofa domesticus) in the Alentejo region of southern Portugal. It was identified as Corynebacterium pseudotuberculosis using biochemical tests, multiplex PCR and Pulsed Field Gel Electrophoresis. After genome sequencing and rpoB phylogeny, the strain was classified as C. ulcerans. To better understand the taxonomy of this strain and improve identification methods, we compared strain PO100/5 to other publicly available genomes from C. diphtheriae group. Taxonomic analysis reclassified it and three others strains as the recently described C. silvaticum, which have been isolated from wild boar and roe deer in Germany and Austria. The results showed that PO100/5 is the first sequenced genome of a C. silvaticum strain from livestock and a different geographical region, has the unique sequence type ST709, and could be could produce the diphtheriae toxin, along with strain 05-13. Genomic analysis of PO100/5 showed four prophages, and eight conserved genomic islands in comparison to C. ulcerans. Pangenome analysis of 38 C. silvaticum and 76 C. ulcerans genomes suggested that C. silvaticum is a genetically homogeneous species, with 73.6% of its genes conserved and a pangenome near to be closed (α > 0.952). There are 172 genes that are unique to C. silvaticum in comparison to C. ulcerans. Most of these conserved genes are related to nutrient uptake and metabolism, prophages or immunity against them, and could be genetic markers for species identification. Strains PO100/5 (livestock) and KL0182T (wild boar) were predicted to be potential human pathogens. This information may be useful for identification and surveillance of this pathogen., Competing Interests: The authors have declared that no competing interests exist.

Background: The evidence of the influence of Kinesio Taping® in changing electromyographic signal intensity of the lumbar musculature in patients with chronic non-specific low back pain (LBP) is very sparse., Objectives: To evaluate if Kinesio Taping® changes the electromyographic signal intensity of the longissimus and iliocostalis muscles in patients with chronic non-specific LBP., Methods: Prospectively registered, three-arm randomized controlled trial with a blinded assessor. Patients were randomly allocated to the following interventions: 1) Kinesio Taping® Group (n=21), where patients received the tape according to the manufacturer's manual; 2) Placebo Group (i.e. normal surgical tape) (n=21); and 3) Non-treatment control Group (n=21). Assessments were performed at baseline, immediately after, and 30min after the intervention. The primary outcome was muscle activity of the iliocostalis and longissimus muscles as measured by surface electromyography. The secondary outcome was pain intensity (measured with a 0-10 Numerical Rating Scale). The effects of treatment were calculated using linear mixed models., Results: A total of 63 patients were recruited. Follow up rate was high (98.4%). Patients were mostly women with moderate levels of pain and disability. Kinesio Taping® was better than the control and placebo groups in only 4 of 96 statistical comparisons, likely reflective of type I error due to multiple comparisons. No statistically significant differences were identified for the immediate reduction in pain intensity between groups., Conclusion: Kinesio Taping® did not change the electromyographic signal intensity of the longissimus and iliocostalis muscles or reduce pain intensity in patients with chronic low back pain. Clinicaltrials.gov: NCT02759757 (https://clinicaltrials.gov/ct2/show/NCT02759757)., (Copyright © 2019 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.)

Mammalian carnivores are considered a key group in maintaining ecological health and can indicate potential ecological integrity in landscapes where they occur. Carnivores also hold high conservation value and their habitat requirements can guide management and conservation plans. The order Carnivora has 84 species from 8 families in the Neotropical region: Canidae; Felidae; Mephitidae; Mustelidae; Otariidae; Phocidae; Procyonidae; and Ursidae. Herein, we include published and unpublished data on native terrestrial Neotropical carnivores (Canidae; Felidae; Mephitidae; Mustelidae; Procyonidae; and Ursidae). NEOTROPICAL CARNIVORES is a publicly available data set that includes 99,605 data entries from 35,511 unique georeferenced coordinates. Detection/non-detection and quantitative data were obtained from 1818 to 2018 by researchers, governmental agencies, non-governmental organizations, and private consultants. Data were collected using several methods including camera trapping, museum collections, roadkill, line transect, and opportunistic records. Literature (peer-reviewed and grey literature) from Portuguese, Spanish and English were incorporated in this compilation. Most of the data set consists of detection data entries (n = 79,343; 79.7%) but also includes non-detection data (n = 20,262; 20.3%). Of those, 43.3% also include count data (n = 43,151). The information available in NEOTROPICAL CARNIVORES will contribute to macroecological, ecological, and conservation questions in multiple spatio-temporal perspectives. As carnivores play key roles in trophic interactions, a better understanding of their distribution and habitat requirements are essential to establish conservation management plans and safeguard the future ecological health of Neotropical ecosystems. Our data paper, combined with other large-scale data sets, has great potential to clarify species distribution and related ecological processes within the Neotropics. There are no copyright restrictions and no restriction for using data from this data paper, as long as the data paper is cited as the source of the information used. We also request that users inform us of how they intend to use the data., (© 2020 The Authors. Ecology © 2020 The Ecological Society of America.)

This study aimed to optimize and validate a multi-residue method for identifying and quantifying pesticides in honey by using both gas and liquid chromatographic separation followed by mass spectrometric detection. The proposed method was validated to detect 168 compounds, 127 of them by LC-MS/MS (liquid chromatography tandem mass spectrometric detection) and 41 by GC-MS/MS (gas chromatography tandem mass spectrometric detection). The limit of detection (LOD) and limit of quantification (LOQ) values for the analytes determined by LC-MS/MS were 0.0001-0.0004 mg/kg and 0.0002-0.0008 mg/kg, respectively. For GC-MS/MS analyses, the LOD and LOQ values were 0.001-0.004 mg/kg and 0.002-0.008 mg/kg. In total, 33 samples of commercial honey produced by apiaries in six Brazilian states were analyzed with the validated method. Residual amounts of 15 analytes were detected in 31 samples (93.9%). The method described in the present study was able to detect an extensive and broad range of pesticides with very high sensitivity.

Question: In people with non-specific low back pain (LBP), what are the effects of photobiomodulation therapy (PBMT) on pain, disability and other outcomes when compared with no intervention, sham PBMT and other treatments, and when used as an adjunct to other treatments?, Design: Systematic review of randomised trials with meta-analysis., Participants: People with acute/subacute or chronic non-specific LBP., Interventions: Any type of PBMT (laser class I, II and III and light-emitting diodes) compared with no treatment, sham PBMT and other types of treatment, or used as an adjunct to another treatment., Outcome Measures: Pain intensity, disability, overall improvement, quality of life, work absence and adverse effects., Results: Twelve randomised controlled trials were included (pooled n = 1,046). Most trials had low risk of bias. Compared with sham PBMT, the effect of PBMT on pain and disability was clinically unimportant in people with acute/subacute or chronic LBP. In people with chronic LBP, there was no clinically important difference between the effect of PBMT and the effect of exercise on pain or disability. Although benefits were observed on some other outcomes, these estimates were imprecise and/or based on low-quality evidence. PBMT was estimated to reduce pain (MD -11.20, 95% CI -20.92 to -1.48) and disability (MD -11.90, 95% CI -17.37 to -6.43) more than ultrasound, but these confidence intervals showed important uncertainty about whether the differences in effect were worthwhile or trivial. Conversely, PBMT was estimated to reduce pain (MD 19.00, 95% CI 9.49 to 28.51) and disability (MD 17.40, 95% CI 8.60 to 26.20) less than Tecar (Energy Transfer Capacitive and Resistive) therapy, with marginal uncertainty that these differences in effect were worthwhile., Conclusion: Current evidence does not support the use of PBMT to decrease pain and disability in people with non-specific LBP., Registration: CRD42018088242., (Copyright © 2020 Australian Physiotherapy Association. Published by Elsevier B.V. All rights reserved.)

Objective: To evaluate the overall confidence in the results of systematic reviews of exercise therapy for chronic non-specific low back pain using the AMSTAR 2 tool., Methods: PubMed, Embase, Cochrane Database of Systematic Reviews, PEDro and CINAHL was searched up to February 2017. Two independent reviewers selected systematic reviews of randomized controlled trials that investigated exercise therapy in patients with low back pain. AMSTAR 2 assessment was performed by pairs of reviewers, and the overall confidence in the results of the systematic reviews were rated as 'High', 'Moderate', 'Low' and 'Critically low'. Descriptive analysis was used to summarize the characteristics of included systematic reviews. The percentage of systematic reviews achieving each item from the AMSTAR 2 and the overall confidence in the results were tabulated., Results: The search identified 38 systematic reviews. Most of the reviews included a median of 10 clinical trials and total sample size of 813 participants per review. Five of 38 (13%) reviews were Cochrane reviews, and 8 (21%) systematic reviews had a protocol published or registered prospectively. The overall confidence in the results of 28 reviews (74%) was rated as 'Critically low', 6 (16%) as 'Low', 1 (2%) as Moderate, while 3 of 38 reviews (8%) were rated as 'High'., Conclusion: The results demonstrate very low confidence in the results of most systematic reviews of exercise in chronic non-specific low back pain. Clinicians are more likely to deliver the most efficacious interventions to patients by critically appraising systematic reviews using AMSTAR 2 before making their decisions., (Copyright © 2019 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.)

Activin-like kinase 5 (ALK-5) is involved in the physiopathology of several conditions, such as pancreatic carcinoma, cervical cancer and liver hepatoma. Cellular events that are landmarks of tumorigenesis, such as loss of cell polarity and acquisition of motile properties and mesenchymal phenotype, are associated to deregulated ALK-5 signaling. ALK-5 inhibitors, such as SB505154, GW6604, SD208, and LY2157299, have recently been reported to inhibit ALK-5 autophosphorylation and induce the transcription of matrix genes. Due to their ability to impair cell migration, invasion and metastasis, ALK-5 inhibitors have been explored as worthwhile hits as anticancer agents. This work reports the development of a structure-based virtual screening (SBVS) protocol aimed to prospect promising hits for further studies as novel ALK-5 inhibitors. From a lead-like subset of purchasable compounds, five molecules were identified as putative ALK-5 inhibitors. In addition, molecular dynamics and binding free energy calculations combined with pharmacokinetics and toxicity profiling demonstrated the suitability of these compounds to be further investigated as novel ALK-5 inhibitors.

Objective: To evaluate if allocation concealment and intention-to-treat (ITT) analysis influence the treatment effects of physical therapy interventions in low back pain (LBP) trials., Data Sources: We searched on PubMed, Embase, Cochrane Database of Systematic Reviews, Physiotherapy Evidence Database (PEDro), and CINAHL up to February 2017., Study Selection: We included LBP trials that compared physical therapy interventions to placebo or no intervention or minimal intervention with pain or disability outcomes., Data Extraction: Information about allocation concealment and ITT analysis was extracted from PEDro and pain and disability outcomes converted to a 0-100 scale. A meta-regression was performed to evaluate the influence of these methodological features of interest on treatment effects. Other covariates included in the meta-regression were sample size and sequence generation., Data Synthesis: We identified 128 eligible trials (pooled N=20,555 participants). A total of 44.5% of the trials achieved allocation concealment, while 32% performed ITT analysis. Meta regression analyses showed no influence of allocation concealment on treatment effects for pain (regression coefficient 0.009; 95% confidence interval [CI] -2.91 to 2.91) and disability (regression coefficient 1.13; 95% CI -1.35 to 3.62), and no influence of ITT analysis for pain (regression coefficient 1.38; 95% CI -1.73 to 4.50) or disability (regression coefficient 1.27; 95% CI -1.39 to 3.64). For the other covariates, there was also no clinically significant influence on the treatment effects., Conclusion: There is no influence of allocation concealment or ITT analysis on treatment effects of physical therapy interventions for pain and disability in LBP trials., (Copyright © 2019 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

The analysis of health policy trajectories contributes to disclose the endogenous and exogenous elements that influence the management of health systems. This article aims to describe the trajectory of the Unified Health System of the Federal District (SUS-DF) from 1960 to 2018 and identify the challenges to expand the capacity for protection and health promotion of the population of the Federal District. A documentary analysis of plans, reports, and articles published from 1959 to 2018 and the collection of secondary data were carried out in databases of DATASUS and the Government of the Federal District. RESULTS The SUS-DF trajectory was delineated through care organization actions, health system management and health care personnel training and development. Health indicators such as infant mortality and life expectancy at birth have shown a positive development. There was an increase in health care servicesupply, with an increase in the number of beds, basic health units and professionals, although insufficient, given the population increase. CONCLUSION the actions indicate the growing complexity of health system management, with challenges related to the adaptation of the capacity to respond to the population'shealth needs and reveal internal potentials in the field of health training.

Baccharis dracunculifolia is a medicinal plant native to southeastern Brazil and is the main botanical source used by bees (Apis mellifera) in the manufacture of green propolis and display similar gastroprotective action and chemical profile. This article reports the healing gastric ulcer activity of the hydroethanolic extract of B. dracunculifolia (HEBD) in an acetic acid-induced ulcer model. In addition to the extract, the isolated compounds ferulic acid, p-coumaric acid, caffeic acid, baccharin, and aromadendrin-4'-O-methyl ether were also assayed. HEBD at a dose of 300 mg/kg reduced the ulcerated area by 49.4% after treatment for 7 days, twice a day. Histological analyses revealed that the margins and base of the ulcer obtained significant regeneration, and periodic acid Schiff base staining showed a 78.2% increase in the mucin levels. The action on the enzymatic antioxidant system demonstrated an increased activity of superoxide dismutase and glutathione-S-transferase, in addition to raising glutathione reduced levels and myeloperoxidase activity. HEBD did not show cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazole bromine test. In vitro, HEBD inhibited the H + /K + -ATPase enzyme and showed antioxidant activity in the 2,2 diphenyl-1-picryllydrazyl test. Regarding the isolated compounds, oral administration of p-coumaric acid (15 mg/kg) reduced the ulcerated area by 66.2%. The results suggest that HEBD recovers the gastric ulcerated tissue, raising mucus and antioxidant enzyme levels, and reducing the H + /K + -ATPase activity. In addition, the findings confirm that p-coumaric acid is a pivotal bioactive compound on the gastric healing effects elicited by HEBD. © 2019 BioFactors, 45(3):479-489, 2019., (© 2019 International Union of Biochemistry and Molecular Biology.)

Introduction: Aerobic exercise programs have been used for various health conditions, including musculoskeletal disorders. However, the literature is still limited regarding the effect of aerobic exercise on pain and disability in patients with chronic non-specific low back pain., Methods: Search strategies will be performed in the following databases: PubMed, EMBASE ( https://www.embase.com ), CINAHL, PEDro, Lilacs, and Cochrane Central Register of Controlled Trials (CENTRAL). We will include randomized controlled trials in any language or date of publication. The primary outcomes will be pain and disability. The methodological quality and statistical reporting of each eligible trial will be evaluated using the 11-item PEDro scale. The strength of the recommendations will be summarized using the using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach., Discussion: This systematic review will provide a synthesis of current evidence on the effects of aerobic exercise in patients with chronic low back pain on pain and disability outcomes. This information can help healthcare professionals in decision-making related to the use of aerobic exercise in patients with low back pain. Following the guidelines, this systematic review protocol was registered on the Prospective International Register of Systematic Reviews (PROSPERO) number CRD42017071945.

Study Design: Systematic review., Objective: To investigate the effects of Kinesio Taping (KT) in patients with nonspecific low back pain., Summary of Background Data: KT is widely used in patients with low back pain., Methods: We conducted searches on PubMed, EMBASE, PEDro, SciELO, and LILACS up to February 26, 2018. We included only randomized controlled trials (RCTs) in adults with chronic nonspecific low back pain that compared KT to no intervention or placebo as well as RCTs that compared KT combined with exercise against exercise alone. The methodological quality and statistical reporting of the eligible trials were measured by the 11-item PEDro scale. The quality of the evidence was assessed using the GRADE classification. We considered pain intensity and disability as the primary outcomes. Whenever possible, the data were pooled through meta-analysis., Results: We identified 11 RCTs for this systematic review (pooled n = 743). Two clinical trials (pooled n = 100) compared KT to no intervention at the short-term follow-up. Four studies compared KT to placebo (pooled n = 287) at short-term follow-up and two trials (pooled n = 100) compared KT to placebo at intermediate-term follow-up. Five trials (pooled n = 296) compared KT combined with exercises or electrotherapy to exercises or spinal manipulation alone. No statistically significant difference was found for most comparisons., Conclusion: Very low to moderate quality evidence shows that KT was no better than any other intervention for most the outcomes assessed in patients with chronic nonspecific low back pain. We found no evidence to support the use of KT in clinical practice for patients with chronic nonspecific low back pain., Level of Evidence: 1.

Background: An updated summary of the evidence for the reliability of the Mechanical Diagnosis and Therapy (MDT) system in patients with spinal pain is needed., Objective: To investigate the evidence on the intrarater and interrater reliability of MDT in patients with spinal pain., Methods: Searches in MEDLINE, CINAHL, Embase, PEDro, and Scopus were conducted for this systematic review. We included any study design as long as reliability of the MDT method was tested in patients with spinal pain. We collected data on the reliability of MDT to identify main and subsyndromes, directional preference, the centralization phenomenon, and lateral shift. The methodological quality of studies was assessed using the Quality Appraisal of Diagnostic Reliability and the Guidelines for Reporting Reliability and Agreement Studies checklists., Results: Twelve studies were included (8 studies on back pain, pooled n = 2160 patients; 3 studies on neck pain, pooled n = 45 patients; and 3 studies recruited mixed spinal conditions, pooled n = 389 patients). Studies investigating patients with back pain reported kappa estimates ranging from 0.26 to 1.00 (main and subsyndromes), 0.27 to 0.90 (directional preference), and 0.11 to 0.70 (centralization phenomenon). Kappa estimates for studies investigating neck pain ranged from 0.47 to 0.84 (main and subsyndromes) and 0.46 (directional preference). In mixed populations, kappa estimates ranged from 0.56 to 0.96 (main and subsyndromes)., Conclusion: The MDT system appears to have acceptable interrater reliability for classifying patients with back pain into main and subsyndromes when applied by therapists who have completed the credentialing examination, but unacceptable reliability in other therapists. We found conflicting evidence regarding the reliability of the MDT system in patients with neck pain or mixed pain locations. J Orthop Sports Phys Ther 2018;48(12):923-933. Epub 22 Jun 2018. doi:10.2519/jospt.2018.7876.

HER-2 and EGFR are biological targets related to the development of cancer and the discovery and/or development of a dual inhibitor could be a good strategy to design an effective drug candidate. In this study, analyses of the chemical properties of a group of substances having affinity for both HER-2 and EGFR were carried out with the aim of understanding the main factors involved in the interaction between these inhibitors and the biological targets. Comparative analysis of molecular interaction fields (CoMFA) and comparative molecular similarity index analysis (CoMSIA) techniques were applied on 63 compounds. From CoMFA analyses, we found for both HER-2 (r² calibration = 0.98 and q² cv = 0.83) and EGFR (r² calibration = 0.98 and q² cv = 0.73) good predictive models. Good models for CoMSIA technique have also been found for HER-2 (r² calibration = 0.92 and q² cv = 0.74) and EGFR (r² calibration = 0.97 and q² cv = 0.72). The constructed models could indicate some important characteristics for the inhibition of the biological targets. New compounds were proposed as candidates to inhibit both proteins. Therefore, this study may guide future projects for the development of new drug candidates for the treatment of breast cancer.

Ethopharmacological Relevance: The propolis is extensively used in folk medicine in natura or to prepare pharmaceutical formulations since ancient time to improve health or prevent diseases, among them gastrointestinal disorders. Aiming to contribute in the scientific validation about the popular use of Brazilian Green propolis (BGP) against gastritis and gastric ulcer, this work evaluated the antiulcer potential of isolated compounds from BGP, three prenylated p-coumaric acid derivatives and two flavonoids, respectively named: 3,5 diprenyl-4-hydroxycinnamic acid (artepillin C) (1), 3-prenyl-4-dihydroxycinnamoiloxy cinnamic acid (baccharin) (2), 3-prenyl-4-hydroxycinnamic acid (drupanin) (3), aromadendrin-4'-O-methyl-ether (4) and kaempferide (5)., Material and Methods: The compounds were characterized by nuclear magnetic resonance and mass spectrometry. Their gastroprotective effects were evaluated against ethanol/HCl- and indomethacin-induced ulcer in mice. Further, histological, histochemical, oxidative and inflammatory parameters were analyzed at ulcerated tissue. Acid antisecretory activities also were also assessed., Results: Compound 2 did not reduce the ethanol/HCl- induced ulcer at 30 mg/kg (p.o), whereas the minimum oral gastroprotective doses of 1, 3, 4 and 5 were 0.3, 0.3, 3 and 3 mg/kg, respectively. Besides, these compounds prevented ethanol/HCl-induced ulcer by intraperitoneal route, as well as indomethacin-induced ulcer by oral route. The gastroprotection was accompanied by normalization of superoxide dismutase, catalase and glutathione-S-transferase activities and reduction in myeloperoxidase activity. Moreover, the compounds 4 and 5 increased the gastric mucin content and 1 reduced TNF amount. Furthermore, 1, 3, 4 and 5 decreased volume, pH, total acidity and pepsin activity of the gastric juice from rats., Conclusions: Together, our findings showed a diversified mode of action elicited by 1, 3, 4 and 5 on the gastroprotection and contribute to explain the anti-ulcer activity reported for BGP., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Activin Receptor-Like Kinase 5 (ALK-5) is related to some types of cancer, such as breast, lung, and pancreas. In this study, we have used molecular docking, molecular dynamics simulations, and free energy calculations in order to explore key interactions between ALK-5 and six bioactive ligands with different ranges of biological activity. The motivation of this work is the lack of crystal structure for inhibitor-protein complexes for this set of ligands. The understanding of the molecular structure and the protein-ligand interaction could give support for the development of new drugs against cancer. The results show that the calculated binding free energy using MM-GBSA, MM-PBSA, and SIE is correlated with experimental data with r 2  = 0.88, 0.80, and 0.94, respectively, which indicates that the calculated binding free energy is in excellent agreement with experimental data. In addition, the results demonstrate that H bonds with Lys232, Glu245, Tyr249, His283, Asp351, and one structural water molecule play an important role for the inhibition of ALK-5. Overall, we discussed the main interactions between ALK-5 and six inhibitors that may be used as starting points for designing new molecules to the treatment of cancer.

The use of silicon in Billbergia zebrina cultivation in vitro is an alternative for optimizing micropropagation of this important ornamental plant species. The objective of the present study was to evaluate the growth and anatomical and physiological alterations in Billbergia zebrina (Herbert) Lindley plants as a function of different sources and concentrations of silicon during in vitro cultivation and acclimatization. The experimental design was completely randomized, with a double factorial arrangement and an additional control treatment (2 x 3 + 1). The first factor was relative to calcium silicate and sodium silicate added to the Murashige & Skoog culture medium; the second factor was related to its concentrations, 0.5, 1.0, and 2.0 mg L-1. After 100 days, their growth, anatomical characteristics, level of silicon and chlorophyll content were evaluated. Growth characteristics were assessed after 60 days of acclimatization period. Plants absorbed more sodium silicate than calcium silicate. This source also stressed the plants impairing their growth, but the highest silicon absorption at 1 mg L-1 attenuated the stressful conditions. The supplementation of the culture medium with calcium silicate led to improved growth, anatomical, and physiological characteristics, which benefited the development of more resistant seedlings with better performance during acclimatization.

In this work, a group of α-keto-based inhibitors of the cruzain enzyme with anti-chagas activity was selected for a three-dimensional quantitative structure-activity relationship study (3D-QSAR) combined with molecular dynamics (MD). Firstly, statistical models based on Partial Least Square (PLS) regression were developed employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) descriptors. Validation parameters (q 2 and r 2 )for the models were, respectively, 0.910 and 0.997 (CoMFA) and 0.913 and 0.992 (CoMSIA). In addition, external validation for the models using a test group revealed r 2 pred  = 0.728 (CoMFA) and 0.971 (CoMSIA). The most relevant aspect in this study was the generation of molecular fields in both favorable and unfavorable regions based on the models developed. These fields are important to interpret modifications necessary to enhance the biological activities of the inhibitors. This analysis was restricted considering the inhibitors in a fixed conformation, not interacting with their target, the cruzain enzyme. Then, MD was employed taking into account important variables such as time and temperature. MD helped describe the behavior of the inhibitors and their properties showed similar results as those generated by QSAR-3D study., (© 2018 John Wiley & Sons A/S.)

Competing Interests: Competing interests: None declared.

Background: The McKenzie Method of Mechanical Diagnosis and Therapy (MDT) is one of the exercise approaches recommended by low back pain (LBP) guidelines. We investigated the efficacy of MDT compared with placebo in patients with chronic LBP., Methods: This was a prospectively registered, two-arm randomised placebo controlled trial, with a blinded assessor. A total of 148 patients seeking care for chronic LBP were randomly allocated to either MDT (n=74) or placebo (n=74). Patients from both groups received 10 treatment sessions over 5 weeks. Patients from both groups also received an educational booklet. Clinical outcomes were obtained at the end of treatment (5 weeks) and 3, 6 and 12 months after randomisation. Primary outcomes were pain intensity and disability at the end of treatment (5 weeks). We also conducted a subgroup analysis to identify potential treatment effect modifiers that could predict a better response to MDT treatment., Results: The MDT group had greater improvements in pain intensity at the end of treatment (mean difference (MD) -1.00, 95% CI -2.09 to -0.01) but not for disability (MD -0.84, 95% CI -2.62 to 0.93). We did not detect between-group differences for any secondary outcomes, nor were any treatment effect modifiers identified. Patients did not report any adverse events., Conclusion: We found a small and likely not clinically relevant difference in pain intensity favouring the MDT method immediately at the end of 5 weeks of treatment but not for disability. No other difference was found for any of the primary or secondary outcomes at any follow-up times., Trial Registration Number: ClinicalTrials.gov (NCT02123394)., Competing Interests: Competing interests: The care provider who treated patients in the MDT group has completed first level McKenzie training, however has no involvement with the McKenzie Institute. This trial did not receive neither funding from McKenzie Institute nor any assistance in writing/analysing the results of this trial. Authors do not have any involvement with the McKenzie Institute. MJH, LOPC and ANG receive funding from International Mechanical Diagnosis and Therapy Research Foundation for the following studies on MDT: (1) Hancock MJ, Maher CG, Mota da Silva T, Clare H, Steffens D (2016). Secondary prevention of a recurrence of low back pain. (2) Hancock MJ, Garcia AN, Costa LdCM, Costa LOP (2014). Identifying patients with back pain who respond best to MDT. MJH is keynote speaker at the 2017 McKenzie conference and his travel costs will be paid., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Association of amlodipine besylate and olmesartan medoxomil in fixed-dose combination tablets is effective, safe and well tolerated for the treatment of hypertension. The aim of this study was to optimize and validate a novel and fast UHPLC-DAD method for simultaneous quantification of these antihypertensive drugs in tablets, using a transfer procedure from a conventional HPLC-DAD method. The HPLC separation was carried out using a C18 column (150 × 4.6 mm2; 5 μm) and a mobile phase composed of acetonitrile, methanol and 0.3% trimethylamine pH 2.75 (30:30:40), at 1.0 mL/min. UV detection was performed at 238 nm and injection volume was 10 μL. Then, the analytical method was transferred to UHPLC, using a BEH C18 column (50 × 2.1 mm2; 1.7 μm). Mathematical equations were applied to calculate the UHPLC mobile phase flow rate and injection volume, which were 0.613 mL/min and 0.7 μL, respectively. UHPLC method was fully validated and showed to be selective, linear (r2 > 0.99), precise (RSD < 2.0%), accurate and robust. UHPLC method was statistically equivalent to the HPLC method after analysis of three batches of BenicarAnlo® tablets. However, UHPLC method promoted faster analyses, better chromatographic performance and lower solvent consumption.

Introduction: Meta-epidemiological studies examining the influence of methodological characteristics, such as allocation concealment and intention-to-treat analysis have been performed in a large number of healthcare areas. However, there are no studies investigating these characteristics in physical therapy interventions for patients with low back pain. The aim of this study is to investigate the influence of allocation concealment and the use of intention-to-treat analysis on estimates of treatment effects of physical therapy interventions in low back pain clinical trials., Methods and Analysis: Searches on PubMed, Embase, Cochrane Database of Systematic Reviews, Physiotherapy Evidence Database (PEDro) and CINAHL databases will be performed. We will search for systematic reviews that include a meta-analysis of randomised controlled trials that compared physical therapy interventions in patients with low back pain with placebo or no intervention, and have pain intensity or disability as the primary outcomes. Information about selection (allocation concealment) and attrition bias (intention-to-treat analysis) will be extracted from the PEDro database for each included trial. Information about bibliographic data, study characteristics, participants' characteristics and study results will be extracted. A random-effects model will be used to provide separate estimates of treatment effects for trials with and without allocation concealment and with and without intention-to-treat analysis (eg, four estimates). A meta-regression will be performed to measure the association between methodological features and treatment effects from each trial. The dependent variable will be the treatment effect (the mean between-group differences) for the primary outcomes (pain or disability), while the independent variables will be the methodological features of interest (allocation concealment and intention-to-treat analysis). Other covariates will include sample size and sequence generation., Ethics and Dissemination: No ethical approval will be required for this study. The study findings will be published in a peer-reviewed journal and presented at international conferences., Registration Number: International Prospective Register of Systematic Reviews (CRD42016052347)., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Cancer cells can expand to other parts of body through blood system and nodes from a mechanism known as metastasis. Due to the large annual growth of cancer cases, various biological targets have been studied and related to this disorder. A very interesting target related to cancer is human epidermal growth factor receptor 2 (HER2). In this study, we analyzed the main intermolecular interactions between a drug used in the cancer treatment (5-fluorouracil) and HER2. Molecular modeling methods were also employed to assess the molecular structure, spectroscopic properties (FTIR and UV-Vis), NBO, QTAIM and HOMO-LUMO energies of 5-FU. From the docking simulations it was possible to analyze the interactions that occur between some residues in the binding site of HER2 and 5-FU. To validate the choice of basis set that was used in the NBO and QTAIM analyses, theoretical calculations were performed to obtain FT-IR and UV/Vis spectra, and the theoretical results are consistent with the experimental data, showing that the basis set chosen is suitable. For the maximum λ from the theoretical calculation (254.89nm) of UV/Vis, the electronic transition from HOMO to LUMO occurs at 4.89eV. From NBO analyses, we observed interactions between Asp863 and 5-FU, i.e. the orbitals with high transfer of electrons are LP O 15 (donor NBO) and BD* (π) N 1 -H 10 (acceptor NBO), being that the value of this interaction is 7.72kcal/mol. Results from QTAIM indicate one main intermolecular H bond, which is necessary to stabilize the complex formed between the ligands and the biological target. Therefore, this study allowed a careful evaluation on the main structural, spectroscopic and electronic properties involved in the interaction between 5-FU and HER2, an important biological complex related to the cancer treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Studies have showed that there are many biological targets related to the cancer treatment, for example, TGF type I receptor (TGF-βRI or ALK5). The ALK5 inhibition is a strategy to treat some types of cancer, such as breast, lung, and pancreas. Here, we performed CoMFA and CoMSIA studies for 70 ligands with ALK5 inhibition. The internal validation for both models (q(2)LOO = 0.887 and 0.822, respectively) showed their robustness, while the external validations showed their predictive power (CoMFA: r(2)test = 0.998; CoMSIA: r(2)test = 0.975). After all validations, CoMFA and CoMSIA maps indicated physicochemical evidences on the main factors involved in the interaction between bioactive ligands and ALK5. Therefore, these results suggest molecular modifications to design new ALK5 inhibitors.

Background: Professional swimmers are often affected by a high number of injuries due to their large amount of training. The occurrence of musculoskeletal pain during an important tournament has not been investigated., Objective: The objective of the study was to assess the prevalence of musculoskeletal pain and its characteristics in professional swimmers. Secondary objectives included evaluating the swimmers' injury history over the previous 12 months, and examining the association of the presence of pain with personal and training characteristics of the swimmers., Design: Observational, cross-sectional study., Method: Two-hundred and fifty-seven swimmers who participated in the Brazilian Swimming Championship were included in the study and answered a questionnaire about personal and training characteristics, presence of pain, and injuries in the previous 12 months. The relative risk of presence of pain was calculated for the following variables: gender, BMI, stroke specialty, swimmer's position, strength training, practice of another physical activity, and previous injuries., Results: The prevalence of musculoskeletal pain was about 20%, with 60% of swimmers reporting at least one injury in the previous 12 months. The shoulder was the most commonly affected region and tendinopathy was the most common type of previous injury. No significant relationships were found between the presence of pain and personal or training characteristics., Conclusions: The results demonstrated that the prevalence of musculoskeletal pain in professional swimmers participating in the most important Brazilian national tournament was approximately 20%, while the majority of participants reported previous injuries in many areas., Level of Evidence: 2c.

Study Design: Systematic review with meta-analysis., Objectives: To determine the biomechanical differences between foot-strike patterns used when running., Background: Strike patterns during running have received attention in the recent literature due to their potential mechanical differences and associated injury risks., Methods: Electronic databases (MEDLINE, Embase, LILACS, SciELO, and SPORTDiscus) were searched through July 2014. Studies (cross-sectional, case-control, prospective, and retrospective) comparing the biomechanical characteristics of foot-strike patterns during running in distance runners at least 18 years of age were included in this review. Two independent reviewers evaluated the risk of bias. A meta-analysis with a random-effects model was used to combine the data from the included studies., Results: Sixteen studies were included in the final analysis. In the meta-analyses of kinematic variables, significant differences between forefoot and rearfoot strikers were found for foot and knee angle at initial contact and knee flexion range of motion. A forefoot-strike pattern resulted in a plantar-flexed ankle position and a more flexed knee position, compared to a dorsiflexed ankle position and a more extended knee position for the rearfoot strikers, at initial contact with the ground. In the comparison of rearfoot and midfoot strikers, midfoot strikers demonstrated greater ankle dorsiflexion range of motion and decreased knee flexion range of motion compared to rearfoot strikers. For kinetic variables, the meta-analysis revealed that rearfoot strikers had higher vertical loading rates compared to forefoot strikers., Conclusion: There are differences in kinematic and kinetic characteristics between foot-strike patterns when running. Clinicians should be aware of these characteristics to help in the management of running injuries and advice on training.