Effects of dietary inclusion of Moringa oleifera leaf meal on growth performance of Muscovy ducklings (Cairina moschata).

OBJECTIVE: The current experiment was performed to investigate the influence of different dietary levels of Moringa oleifera leaf meal (MOLM) on productive performance, nutrient digestibility, blood parameters, immune response, caecal microbiota, and carcass characteristics of Muscovy ducks (Cairina moschata) during 7 to 63 d of age. METHODS: A total of 240 unsexed 7-d-old ducklings were distributed into five (treatment) groups; each one contained six replicates with eight ducklings each. Birds of the first group were fed basal diet without MOLM and served as control, while the other four groups were fed basal diet with 0.25%, 0.50%, 1.0%, and 2.0% MOLM inclusion level, respectively. RESULTS: The obtained results revealed that including MOLM in the diets significantly improved body weight, body weight gain, feed conversion ratio and economic efficiency compared with the control group. Among the different MOLM inclusion treatments, increasing MOLM inclusion level decreased (p<0.05) such previous parameters. Decreasing MOLM inclusion levels in duckling diets increased (p>0.05) the digestibility of organic matter, crude protein, ether extract, and nitrogen free extract, however all MOLM treatments were significantly higher than the control group. Results also revealed that feeding ducks lower MOLM inclusion levels (0.25% or 0.50%) improved blood parameters (p<0.05) compared with the higher inclusion levels (1.0% or 2.0% MOLM) and the control group. Ducks fed different MOLM levels had significantly higher phagocyte index and activity, immunoglobulin G (IgG), IgM, total antioxidant capacity, glutathione peroxidase activity, and superoxide dismutase activity compared with control group. CONCLUSION: Despite the beneficial effects of all MOLM treatments on growth performance, nutrient digestibility, physiological status, and immune response of duckling, the increasing MOLM inclusion level in the diet had deleterious effects on such studied traits, consequently 0.25% was the best MOLM inclusion level in duckling diets.

Importance of TREC and KREC as molecular markers for immunological evaluation of down syndrome children.

Recurrent and severe infections occurred in children with Down Syndrome (DS) due to immunological parameter defects have been reported. The aim of the study is to evaluate the importance of using T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) as molecular markers for immunological investigation of children with DS. The study included 40 non-disjunction trisomy 21 confirmed DS children, and 25 healthy controls. Peripheral blood (PB) was analyzed for lymphocyte subpopulations by flow cytometry, serum immunoglobulin levels, and TREC and KREC copy numbers using quantitative real-time PCR. DS patients showed significantly lower absolute counts of PB T lymphocytes, T helper lymphocytes, T cytotoxic lymphocytes, B lymphocytes, and Natural killer cells, and lower serum IgA, IgG, and IgM levels compared to healthy controls. Copy number of TREC and KREC showed no significant differences between DS patients and healthy controls. There is a significant positive correlation between TREC copy number with a percentage and absolute count of helper T lymphocytes in patients. Also, the KREC copy number was significantly negatively correlated with the age of patients. These findings suggest that copy numbers of TREC and KREC could be useful as molecular markers for immunological evaluation of patients with DS.

Endovascular thrombectomy with or without thrombolysis bridging in patients with acute ischaemic stroke: protocol for a systematic review, meta-analysis of randomised trials and cost-effectiveness analysis.

INTRODUCTION: Current published guidelines and meta-analyses comparing endovascular thrombectomy (EVT) alone versus EVT with bridging intravenous thrombolysis (IVT) suggest that EVT alone is non-inferior to EVT with bridging thrombolysis in achieving favourable functional outcome. Because of this controversy, we aimed to systematically update the evidence and meta-analyse data from randomised trials comparing EVT alone versus EVT with bridging thrombolysis, and performed an economic evaluation comparing both strategies. METHODS AND ANALYSIS: We will conduct a systematic review of randomised controlled trials comparing EVT with or without bridging thrombolysis in patients presenting with large vessel occlusions. We will identify eligible studies by systematically searching the following databases from inception without any language restrictions: MEDLINE (through Ovid), Embase and the Cochrane Library. The following criteria will be used to assess eligibility for inclusion: (1) adult patients ≥18 years old; (2) randomised patients to EVT alone or to EVT with IVT; and (3) measured outcomes, including functional outcomes, at least 90 days after randomisation. Pairs of reviewers will independently screen the identified articles, extract information and assess the risk of bias of eligible studies. We will use the Cochrane Risk-of-Bias tool to evaluate risk of bias. We will also use the Grading of Recommendations, Assessment, Development and Evaluation approach to assess the certainty in evidence for each outcome. We will then perform an economic evaluation based on the extracted data. ETHICS AND DISSEMINATION: This systematic review will not require a research ethics approval because no confidential patient data will be used. We will disseminate our findings by publishing the results in a peer-reviewed journal and via presentation at conferences. PROSPERO REGISTRATION NUMBER: CRD42022315608.

Salix babylonica L. mitigates pancreatic damage by regulating the Beclin-P62/SQSTM1 autophagy pathway in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Salix babylonica L. belongs to the genus Salix, family Salicaceae. It is traditionally used as an antipyretic, antirheumatic, antidiabetic and for the treatment of ulcers and parasite skin diseases. It also has a range of pharmacological effects, such as anti-inflammatory, anti-tumor, antioxidant, and antibacterial effects. However, there are no reports on the phytochemical profile and efficacy of its leaves extract to modulate dexamethasone induced pancreatic damage. AIM OF THE STUDY: The present study was performed to annotate the phytoconstituents of Salix babylonica leaf extract and explore whether and how it could modulate dexamethasone-induced pancreatic damage and the role of oxidative stress and autophagy in mediating its protective effects. MATERIALS AND METHODS: Wistar rats were used for this study. Salix babylonica in two dose levels (100 and 200 mg/kg) or metformin (50 mg/kg) was given by oral gavage concurrently with dexamethasone which was injected SC in a dose of 10 mg/kg for 4 consecutive days. RESULTS: LC-MS analysis furnished 84 secondary metabolites belonging to phenolic acids, salicinoids, proanthocyanidins, flavonoids, cyclohexanediol glycosides, and hydroxy fatty acids. S. babylonica at both dose levels and metformin decreased the elevated pancreatic beclin while elevated the decreased pancreatic P62/SQSTM1 content compared to dexamethasone. These effects were associated with improved histopathological changes, glycemic and lipid parameters indicating that there might be a connection between autophagy and dexamethasone-induced pancreatic damage. Given that the level of GSH was negatively correlated with the levels of beclin and positively correlated with P62/SQSTM1, while both MDA and NO levels were positively correlated with beclin and negatively correlated with P62/SQSTM1, it seems that dexamethasone induced autophagy may be attributed to dexamethasone induced pancreatic oxidative stress. CONCLUSION: Our results indicate that S. babylonica protects pancreatic tissues against dexamethasone-induced damage by decreasing oxidative stress and its associated autophagy. Our study reveals a new mechanism for dexamethasone effects on pancreas and shows the potential therapeutic role of S. babylonica in mitigating dexamethasone adverse effects on pancreas and establishes the groundwork for future clinical applications.

DFT study of adsorbing SO2, NO2, and NH3 gases based on pristine and carbon-doped Al24N24 nanocages.

The adsorption of SO2, NO2, and NH3 toxic gases on Al24N24 and Al24N23C nanocages was investigated by using density functional theory (DFT) calculations. The adsorption energies, frontier orbitals, charge transfer using natural bonding orbital (NBO) analysis, dipole moment, the partial density of states (PDOS), thermodynamic relationships, non-covalent interaction (NCI), and quantum theory of atoms in molecules (QTAIM) were considered. The results reveal that carbon-doped Al24N24 nanocage increases the adsorption energies for SO2 and NO2 gases while decreasing the adsorption energy of NH3 gas. The ΔG for all configurations were negative except the configurations A1 and G2 confirming the weak adsorption of these two complexes. In conclusion, Al24N24 and Al24N23C nanocages are in general promising adsorbents for the removal of SO2, NO2, and NH3 toxic gases. The Al24N24 and Al24N23C nanocages are ideal electronic materials.

Phytoestrogen ß-Sitosterol Exhibits Potent In Vitro Antiviral Activity against Influenza A Viruses.

Influenza is a contagious infection in humans that is caused frequently by low pathogenic seasonal influenza viruses and occasionally by pathogenic avian influenza viruses (AIV) of H5, H7, and H9 subtypes. Recently, the clinical sector in poultry and humans has been confronted with many challenges, including the limited number of antiviral drugs and the rapid evolution of drug-resistant variants. Herein, the anti-influenza activities of various plant-derived phytochemicals were investigated against highly pathogenic avian influenza A/H5N1 virus (HPAIV H5N1) and seasonal low pathogenic human influenza A/H1N1 virus (LPHIV H1N1). Out of the 22 tested phytochemicals, the steroid compounds ß-sitosterol and ß-sitosterol-O-glucoside have very potent activity against the predefined influenza A viruses (IAV). Both steroids could induce such activity by affecting multiple stages during IAV replication cycles, including viral adsorption and replication with a major and significant impact on the virus directly in a cell-free status "viricidal effect". On a molecular level, several molecular docking studies suggested that ß-sitosterol and ß-sitosterol-O-glucoside exhibited viricidal effects through blocking active binding sites of the hemagglutinin surface protein, as well as showing inhibitory effects against replication through the binding with influenza neuraminidase activity and blocking the active sites of the M2 proton channel activity. The phytoestrogen ß-sitosterol has structural similarity with the active form of the female sex hormone estradiol, and this similarity is likely one of the molecular determinants that enables the phytoestrogen ß-sitosterol and its derivative to control IAV infection in vitro. This promising anti-influenza activity of ß-sitosterol and its O-glycoside derivative, according to both in vitro and cheminformatics studies, recommend both phytochemicals for further studies going through preclinical and clinical phases as efficient anti-influenza drug candidates.

Apple (Malus domestica Borkh) leaves attenuate indomethacin-induced gastric ulcer in rats.

Malus domestica Borkh, the apple tree, exhibited numerous pharmacological properties including antioxidant, neuroprotective, anti-inflammatory, anticancer and antimicrobial activities. The present work aimed to annotate the secondary metabolites from a butanol fraction of apple leaves (BLE), evaluate the gastro-protective and healing effects of this fraction against indomethacin-induced gastric ulcers in rats and to identify its mechanism of action. BLE (100, and 200 mg/kg) was orally administered in rats as an acute treatment against indomethacin-induced gastric ulcer in comparison with famotidine as reference anti-ulcer drug. The stomachs of rats were collected to determine the ulcer index, the preventive ratio, measure the activity of glutathione peroxidase (GPx), and estimate the expression of cyclooxygenase-2 (COX-2), and heat shock protein 70 (HSP70). Furthermore, we evaluated both inflammatory and oxidative stress markers in the gastric tissues. We also performed histopathological study of gastric mucosa using H&E stain and periodic Schiff base stain to evaluate both gastric injury scores and gastric mucus content respectively. Pretreatment with BLE markedly lowered the severity of gastric injury induced by indomethacin, decreased oxidative stress, inflammatory cytokines, and COX-2 expression in the examined gastric tissues. The gastric healing effect of BLE was associated with increased mucoglycoproteins, and HSP70 expression. Additionally, gastric healing effect of high dose of BLE was superior to that of famotidine in decreasing gastric injury scores, COX-2, inflammatory cytokines, lipid peroxidation and in increasing gastric mucin content, HSP70, and reduced glutathione. These findings indicate that BLE is effective in accelerating ulcer healing by boosting HSP70 expression, and decreasing COX-2 expression, oxidative stress, and gastric inflammation which might be related to the presence of 21 phytoconstituents.

The life and death of living systematic reviews: a methodological survey.

OBJECTIVES: The objectives of this study are to describe the characteristics of living systematic reviews (LSRs) and to understand their life cycles. STUDY DESIGN AND SETTING: We conducted a comprehensive search up to April 2021 then selected articles and abstracted data in duplicate and independently. We undertook descriptive analyses and calculated delay in version update and delay since the last published version. RESULTS: We included 76 eligible LSRs with a total of 279 eligible versions. The majority of LSRs was from the clinical field (70%), was COVID-19 related (63%), and had a funding source specified (62%). The median number of versions per LSR was 2 (interquartile range (IQR) 1-4; range 1-19). The median and IQR for the ratio of the actual period of update to the planned period of update was 1.12 (0.81; 1.71). Out of all reviews with a 'planned period of update' and at least one update (N = 19), eight LSRs (42%) had a period since last published version greater than 3 times the planned period of update. No LSR included a 'retirement notice' in their latest published version. CONCLUSION: While most LSR complied with the planned period of producing updates, a substantive proportion lagged since their last update.

Inspiratory muscle training, with or without concomitant pulmonary rehabilitation, for chronic obstructive pulmonary disease (COPD).

BACKGROUND: Inspiratory muscle training (IMT) aims to improve respiratory muscle strength and endurance. Clinical trials used various training protocols, devices and respiratory measurements to check the effectiveness of this intervention. The current guidelines reported a possible advantage of IMT, particularly in people with respiratory muscle weakness. However, it remains unclear to what extent IMT is clinically beneficial, especially when associated with pulmonary rehabilitation (PR).   OBJECTIVES: To assess the effect of inspiratory muscle training (IMT) on chronic obstructive pulmonary disease (COPD), as a stand-alone intervention and when combined with pulmonary rehabilitation (PR). SEARCH METHODS: We searched the Cochrane Airways trials register, CENTRAL, MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO, Physiotherapy Evidence Database (PEDro) ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform on 20 October 2021. We also checked reference lists of all primary studies and review articles. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared IMT in combination with PR versus PR alone and IMT versus control/sham. We included different types of IMT irrespective of the mode of delivery. We excluded trials that used resistive devices without controlling the breathing pattern or a training load of less than 30% of maximal inspiratory pressure (PImax), or both. DATA COLLECTION AND ANALYSIS: We used standard methods recommended by Cochrane including assessment of risk of bias with RoB 2. Our primary outcomes were dyspnea, functional exercise capacity and health-related quality of life.  MAIN RESULTS: We included 55 RCTs in this review. Both IMT and PR protocols varied significantly across the trials, especially in training duration, loads, devices, number/ frequency of sessions and the PR programs. Only eight trials were at low risk of bias. PR+IMT versus PR We included 22 trials (1446 participants) in this comparison. Based on a minimal clinically important difference (MCID) of -1 unit, we did not find an improvement in dyspnea assessed with the Borg scale at submaximal exercise capacity (mean difference (MD) 0.19, 95% confidence interval (CI) -0.42 to 0.79; 2 RCTs, 202 participants; moderate-certainty evidence).   We also found no improvement in dyspnea assessed with themodified Medical Research Council dyspnea scale (mMRC) according to an MCID between -0.5 and -1 unit (MD -0.12, 95% CI -0.39 to 0.14; 2 RCTs, 204 participants; very low-certainty evidence).  Pooling evidence for the 6-minute walk distance (6MWD) showed an increase of 5.95 meters (95% CI -5.73 to 17.63; 12 RCTs, 1199 participants; very low-certainty evidence) and failed to reach the MCID of 26 meters. In subgroup analysis, we divided the RCTs according to the training duration and mean baseline PImax. The test for subgroup differences was not significant. Trials at low risk of bias (n = 3) demonstrated a larger effect estimate than the overall. The summary effect of the St George's Respiratory Questionnaire (SGRQ) revealed an overall total score below the MCID of 4 units (MD 0.13, 95% CI -0.93 to 1.20; 7 RCTs, 908 participants; low-certainty evidence).  The summary effect of COPD Assessment Test (CAT) did not show an improvement in the HRQoL (MD 0.13, 95% CI -0.80 to 1.06; 2 RCTs, 657 participants; very low-certainty evidence), according to an MCID of -1.6 units.  Pooling the RCTs that reported PImax showed an increase of 11.46 cmH2O (95% CI 7.42 to 15.50; 17 RCTs, 1329 participants; moderate-certainty evidence) but failed to reach the MCID of 17.2 cmH2O.  In subgroup analysis, we did not find a difference between different training durations and between studies judged with and without respiratory muscle weakness.  One abstract reported some adverse effects that were considered "minor and self-limited". IMT versus control/sham Thirty-seven RCTs with 1021 participants contributed to our second comparison. There was a trend towards an improvement when Borg was calculated at submaximal exercise capacity (MD -0.94, 95% CI -1.36 to -0.51; 6 RCTs, 144 participants; very low-certainty evidence). Only one trial was at a low risk of bias. Eight studies (nine arms) used the Baseline Dyspnea Index - Transition Dyspnea Index (BDI-TDI). Based on an MCID of +1 unit, they showed an improvement only with the 'total score' of the TDI (MD 2.98, 95% CI 2.07 to 3.89; 8 RCTs, 238 participants; very low-certainty evidence). We did not find a difference between studies classified as with and without respiratory muscle weakness. Only one trial was at low risk of bias. Four studies reported the mMRC, revealing a possible improvement in dyspnea in the IMT group (MD -0.59, 95% CI -0.76 to -0.43; 4 RCTs, 150 participants; low-certainty evidence). Two trials were at low risk of bias. Compared to control/sham, the MD in the 6MWD following IMT was 35.71 (95% CI 25.68 to 45.74; 16 RCTs, 501 participants; moderate-certainty evidence). Two studies were at low risk of bias. In subgroup analysis, we did not find a difference between different training durations and between studies judged with and without respiratory muscle weakness.  Six studies reported theSGRQ total score, showing a larger effect in the IMT group (MD -3.85, 95% CI -8.18 to 0.48; 6 RCTs, 182 participants; very low-certainty evidence). The lower limit of the 95% CI exceeded the MCID of -4 units. Only one study was at low risk of bias. There was an improvement in life quality with CAT (MD -2.97, 95% CI -3.85 to -2.10; 2 RCTs, 86 participants; moderate-certainty evidence). One trial was at low risk of bias. Thirty-two RCTs reported PImax, showing an improvement without reaching the MCID (MD 14.57 cmH2O, 95% CI 9.85 to 19.29; 32 RCTs, 916 participants; low-certainty evidence). In subgroup analysis, we did not find a difference between different training durations and between studies judged with and without respiratory muscle weakness.   None of the included RCTs reported adverse events. AUTHORS' CONCLUSIONS: IMT may not improve dyspnea, functional exercise capacity and life quality when associated with PR. However, IMT is likely to improve these outcomes when provided alone. For both interventions, a larger effect in participants with respiratory muscle weakness and with longer training durations is still to be confirmed.

Vasorelaxant Effects of Syzygium samarangense (Blume) Merr. and L.M.Perry Extract Are Mediated by NO/cGMP Pathway in Isolated Rat Thoracic Aorta.

Syzygium samarangense (Blume) Merr. and L.M.Perry is utilized widely in traditional medicine. We have reported previously a wide array of pharmacological properties of its leaf extract, among them anti-inflammatory, antioxidant, hepatoprotective, antidiabetic, antiulcer, and antitrypanosomal activities. We also annotated its chemical composition using LC-MS/MS. Here, we continue our investigations and evaluate the vasorelaxant effects of the leaf extract on aortic rings isolated from rats and explore the possible underlying mechanisms. S. samarangense extract induced a concentration dependent relaxation of the phenylephrine-precontracted aorta in the rat model. However, this effect disappeared upon removing the functional endothelium. Pretreating the aortic tissues either with propranolol or NG-nitro-L-arginine methyl ester inhibited the relaxation induced by the extract; however, atropine did not affect the extract-induced vasodilation. Meanwhile, adenylate cyclase inhibitor, MDL; specific guanylate cyclase inhibitor, ODQ; high extracellular KCl; and indomethacin as cyclooxygenase inhibitor inhibited the extract-induced vasodilation. On the other hand, incubation of S. samarangense extract with aortae sections having their intact endothelium pre-constricted using phenylephrine or KCl in media free of Ca2+ showed no effect on the constriction of the aortae vessels induced by Ca2+. Taken together, the present study suggests that S. samarangense extract dilates isolated aortic rings via endothelium-dependent nitric oxide (NO)/cGMP signaling. The observed biological effects could be attributed to its rich secondary metabolites. The specific mechanisms of the active ingredients of S. samarangense extract await further investigations.

Robust Antiviral Activity of Santonica Flower Extract (Artemisia cina) against Avian and Human Influenza A Viruses: In Vitro and Chemoinformatic Studies.

The evolution of drug-resistant viral strains following natural acquisition of resistance mutations is a major obstacle to antiviral therapy. Besides the improper prescription of the currently licensed anti-influenza medications, M2-blockers and neuraminidase inhibitors, to control poultry outbreaks/infections potentiates the emergence of drug-resistant influenza variants. Therefore, there is always a necessity to find out new alternatives with potent activity and high safety. Plant extracts and plant-based chemicals represent a historical antiviral resource with remarkable safety in vitro and in vivo to control the emerging and remerging health threats caused by viral infections. Herein, a panel of purified plant extracts and subsequent plant-derived chemicals were evaluated for their anti-avian influenza activity against zoonotic highly pathogenic influenza A/H5N1 virus. Interestingly, santonica flower extract (Artemisia cina) showed the most promising anti-H5N1 activity with a highly safe half-maximal cytotoxic concentration 50 (CC50 > 10 mg/mL) and inhibitory concentration 50 (IC50 of 3.42 µg/mL). To confirm the anti-influenza activity, we assessed the anti-influenza activity of the selected plant extracts against seasonal human influenza A/H1N1 virus and we found that santonica flower extract showed a robust anti-influenza activity that was comparable to the activity against influenza A/H5N1. Furthermore, the mode of action for santonica flower extract with strong inhibitory activity on the abovementioned influenza strains was elucidated, showing a virucidal effect. To go deeper about the activity of the chemometric component of the extract, the major constituent, santonin, was further selected for in vitro screening against influenza A/H5N1 (IC50 = 1.701 µg/mL) and influenza A/H1N1 (IC50 = 2.91 µg/mL). The oxygen of carbonyl functionality in the cyclohexene ring succeeded to form a hydrogen bond with the neuraminidase active site. Despite the fact that santonin revealed similarity to both reference neuraminidase inhibitors in forming hydrogen bonds with essential amino acids, it illustrated shape alignment to oseltamivir more than zanamivir according to Tanimoto algorithms. This study highlights the applicability of santonica flower extract as a promising natural antiviral against low and highly pathogenic influenza A viruses.

Black pepper oil (Piper nigrum L.) mitigates dexamethasone induced pancreatic damage via modulation of oxidative and nitrosative stress.

Dexamethasone acts as an immunosuppressive drug and has been used recently in the management of specific coronavirus disease 2019 (COVID-19) cases; however, various adverse effects could limit its use. In this work, we studied the mitigation effects of black pepper oil (BP oil) on glycemic parameters, dyslipidemia, oxidative and nitrosative stress and pancreatic fibrosis in dexamethasone-treated rats. Animals were divided into five groups that were treated with vehicle, dexamethasone (10 mg/kg, SC) or black pepper oil (BP oil, 0.5 mL, or 1 mL/kg) or metformin (50 mg/kg) plus dexamethasone for 4 consecutive days. Serum insulin, blood glucose, total cholesterol, triglycerides, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) were higher in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic nitric oxide, inducible nitric oxide synthase and malondialdehyde levels were increased in the dexamethasone group vs the control group and decreased in BP oil and metformin groups relative to the dexamethasone group. Pancreatic endothelial nitric oxide synthase and reduced glutathione were declined in the dexamethasone group vs the control group. They were increased in BP oil and metformin groups relative to the dexamethasone group. Moreover, the pancreatic islets diameter and collagen deposition were assessed and found to be higher in the dexamethasone group vs the control group. BP oil and metformin groups showed to regress this effect. In conclusion, BP oil may alleviate hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia and pancreatic structural derangements and fibrosis by suppressing oxidative stress, increasing endogenous antioxidant levels, modulating nitric oxide signaling, preventing pancreatic stellate cells transition and collagen deposition.

Abdominal Visceral Adipose Tissue and All-Cause Mortality: A Systematic Review.

Introduction: Increased abdominal visceral adipose tissue (VAT) implies an adverse cardio-metabolic profile. We examined the association of abdominal VAT parameters and all-cause mortality risk. Methods: We systematically searched four databases. We performed citations/articles screening, data abstraction, and quality assessment in duplicate and independently (CRD42020205021). Results: We included 12 cohorts, the majority used computed tomography to assess abdominal VAT area. Six cohorts with a mean age ≤ 65 years, examining all-cause mortality risk per increment in VAT area (cm2) or volume (cm3), showed a 11-98% relative risk increase with higher VAT parameters. However, the association lost significance after adjusting for glycemic indices, body mass index, or other fat parameters. In 4 cohorts with a mean age >65 years, the findings on mortality were inconsistent. Conversely, in two cohorts (mean age 73-77 years), a higher VAT density, was inversely proportional to VAT area, and implied a higher mortality risk. Conclusion: A high abdominal VAT area seems to be associated with increased all-cause mortality in individuals ≤ 65 years, possibly mediated by metabolic complications, and not through an independent effect. This relationship is weaker and may reverse in older individuals, most likely secondary to confounding bias and reverse causality. An individual participant data meta-analysis is needed to confirm our findings, and to define an abdominal VAT area cutoff implying increased mortality risk. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=205021, identifier CRD42020205021.

A Framework for the Development of Living Practice Guidelines in Health Care.

BACKGROUND: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. OBJECTIVE: To develop a framework that characterizes the processes of development of living practice guidelines in health care. DESIGN: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. SETTING: International. PARTICIPANTS: Multidisciplinary group of 51 persons who have experience with guidelines. MEASUREMENTS: Not applicable. RESULTS: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. LIMITATION: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. CONCLUSION: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. PRIMARY FUNDING SOURCE: None.

Long Term Weight Loss Diets and Obesity Indices: Results of a Network Meta-Analysis.

Background: Scientists have been investigating efficient interventions to prevent and manage obesity. This network meta-analysis (NMA) compared the effect of different diets [moderate macronutrients (MMs), low fat/high carbohydrate (LFHC), high fat/low carbohydrate (HFLC), and usual diet (UD)] on weight, body mass index (BMI), and waist circumference (WC) changes at ≥12 months. Methods: We searched Medline, Embase, PubMed databases, and the Cochrane Library. We systematically assessed randomized controlled trials (RCTs) evaluating dietary interventions on adults (mean BMI ≥ 25 kg/m2) receiving active dietary counseling for ≥12 months. We pooled the data using a random-effect NMA. We assessed the quality of the included RCTs using the Cochrane risk of bias (ROB) tool. Results: We included 36 trials, 14 of which compared HFLC with MM diets. Compared with UD, all diets were associated with a significant weight loss (WL) at ≥12 months, HFLC [mean difference in kg (95% CI): -5.5 (-7.6; -3.4)], LFHC [-5.0 (-7.1; -2.9)] and MM [-4.7 (-6.8; -2.7)]. HFLC, compared with MM diet, was associated with a slightly higher WL (of -0.77 kg) and drop in BMI (of -0.36 kg/m2), while no significant difference was detected in other dietary comparisons. WC was lower with all diets compared to UD, with no significant difference across specific diets. There was no significant interaction of the results with the pre-specified sub-groups. The ROB was moderate to high, mostly related to unclear allocation concealment, high dropout rate and unclear or lack of blinding of participants, providers, and outcome assessors. Conclusion: Dietary interventions extending over ≥12 months are superior to UD in inducing weight, BMI and WC loss. HFLC might be associated with a slightly higher WL compared with MM diets. Systematic Trial Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=103116, PROSPERO (CRD42018103116).

Adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir when used for COVID-19: systematic review and meta-analysis of randomised trials.

BACKGROUND: To summarise specific adverse effects of remdesivir, hydroxychloroquine and lopinavir/ritonavir in patients with COVID-19. METHODS: We searched 32 databases through 27 October 2020. We included randomised trials comparing any of the drugs of interest to placebo or standard care, or against each other. We conducted fixed-effects pairwise meta-analysis and assessed the certainty of evidence using the grading of recommendations assessment, development and evaluation approach. RESULTS: We included 16 randomised trials which enrolled 8152 patients. For most interventions and outcomes the certainty of the evidence was very low to low except for gastrointestinal adverse effects from hydroxychloroquine, which was moderate certainty. Compared with standard care or placebo, low certainty evidence suggests that remdesivir may not have an important effect on acute kidney injury (risk difference (RD) 8 fewer per 1000, 95% CI 27 fewer to 21 more) or cognitive dysfunction/delirium (RD 3 more per 1000, 95% CI 12 fewer to 19 more). Low certainty evidence suggests that hydroxychloroquine may increase the risk of cardiac toxicity (RD 10 more per 1000, 95% CI 0 more to 30 more) and cognitive dysfunction/delirium (RD 33 more per 1000, 95% CI 18 fewer to 84 more), whereas moderate certainty evidence suggests hydroxychloroquine probably increases the risk of diarrhoea (RD 106 more per 1000, 95% CI 48 more to 175 more) and nausea and/or vomiting (RD 62 more per 1000, 95% CI 23 more to 110 more) compared with standard care or placebo. Low certainty evidence suggests lopinavir/ritonavir may increase the risk of diarrhoea (RD 168 more per 1000, 95% CI 58 more to 330 more) and nausea and/or vomiting (RD 160 more per 1000, 95% CI 100 more to 210 more) compared with standard care or placebo. DISCUSSION: Hydroxychloroquine probably increases the risk of diarrhoea and nausea and/or vomiting and may increase the risk of cardiac toxicity and cognitive dysfunction/delirium. Lopinavir/ritonavir may increase the risk of diarrhoea and nausea and/or vomiting. Remdesivir may have no important effect on risk of acute kidney injury or cognitive dysfunction/delirium. These findings provide important information to support the development of evidence-based management strategies for patients with COVID-19.

Pentagalloyl Glucose, a Major Compound in Mango Seed Kernel, Exhibits Distinct Gastroprotective Effects in Indomethacin-Induced Gastropathy in Rats via Modulating the NO/eNOS/iNOS Signaling Pathway.

Gastric ulcers are a common health disorder that affect up to 10% of the world's population. The gastroprotective potential of pentagalloyl glucose (PGG) against indomethacin-induced ulcer in rats and the possible underlying mechanisms were investigated. Gastric ulceration was induced by indomethacin (single dose, 60 mg/kg). Pretreatment with PGG (100 or 200 mg/kg, orally) for 8 days prior to the administration of indomethacin furnished significant reductions in gastric mucosal lesions as well as a significant increase in mucus concentration. Also, PGG significantly declined the elevations in gastric mucosal MDA, TNF-α, IL-6, PECAM-1, VEGF, and iNOS expression. It also mitigated the decrease in GSH and GPx and eNOS expression observed with indomethacin. The protective effects furnished by PGG were comparable to that of famotidine. The obtained results suggested that the anti-ulcer effects of PGG are mediated by increasing mucus production, scavenging free radicals, decreasing inflammation, and attenuating the NO/NOS signaling in favor of eNOS. To sum up, PGG could provide a potential therapy for gastric ulcer after evaluating its efficacy and effectiveness.

Safety and Readmission in Pediatric Ambulatory Surgery in a Tertiary Hospital.

OBJECTIVES: To assess the safety and outcome of pediatric ambulatory surgery by measuring the rate of complications and readmission and identifying common risk factors for complications and readmission. MATERIALS AND METHODS: A cross-sectional study was conducted at King Abdullah Specialist Children's Hospital (KASCH), Riyadh, Kingdom of Saudi Arabia, using the BESTCare 2.0 Health Information System (SKHIC, Riyadh, Saudi Arabia). All cases admitted under the pediatric ambulatory surgery unit from June 2015 to May 2018 were included. We reviewed 462 medical charts and recorded the variables of age, sex, American Society of Anesthesiologists (ASA) classification, complications, and readmission within one month of the surgery. SPSS (IBM Corp., Armonk, NY, USA) was used for data analysis. Associations between exposure variables (e.g., age, duration of surgery) and the outcome variables (e.g., rate of readmission and complications) were measured using the Chi-square test for categorical variables, the T-test and analysis of variance (ANOVA) for numerical and categorical variables, and logistic regression for multiple variables to control confounding variables. RESULTS: Approximately, 3.5% of the pediatric ambulatory surgery cases required readmission, and 10.6% of the patients had complications with zero mortality. All the variables had no significant association either with the readmission or complications (p > 0.05), except for the duration of surgery in minutes which was associated with complications (OR 1.006, 95% CI, 1.000-1.012, P = 0.035). CONCLUSION:  Among pediatric ambulatory surgery cases, the mortality rate is 0%, with low complications and readmission rates. Also, the longer the surgery, the higher the risk of complications.

Use of tocilizumab and sarilumab alone or in combination with corticosteroids for covid-19: systematic review and network meta-analysis.

Objective: To compare the effects of interleukin 6 receptor blockers, tocilizumab and sarilumab, with or without corticosteroids, on mortality in patients with covid-19. Design: Systematic review and network meta-analysis. Data sources: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses (up to 9 June 2021). Review methods: Trials in which people with suspected, probable, or confirmed covid-19 were randomised to interleukin 6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. The analysis used a bayesian framework and assessed the certainty of evidence using the GRADE approach. Results from the fixed effect meta-analysis were used for the primary analysis. Results: Of 45 eligible trials (20 650 patients) identified, 36 (19 350 patients) could be included in the network meta-analysis. Of 36 trials, 27 were at high risk of bias, primarily due to lack of blinding. Tocilizumab, in combination with corticosteroids, suggested a reduction in the risk of death compared with corticosteroids alone (odds ratio 0.79, 95% credible interval 0.70 to 0.88; 35 fewer deaths per 1000 people, 95% credible interval 52 fewer to 18 fewer per 1000; moderate certainty of evidence), as did sarilumab in combination with corticosteroids, compared with corticosteroids alone (0.73, 0.58 to 0.92; 43 fewer per 1000, 73 fewer to 12 fewer; low certainty). Tocilizumab and sarilumab, each in combination with corticosteroids, appeared to have similar effects on mortality when compared with each other (1.07, 0.86 to 1.34; eight more per 1000, 20 fewer to 35 more; low certainty). The effects of tocilizumab (1.12, 0.91 to 1.38; 20 more per 1000, 16 fewer to 59 more; low certainty) and sarilumab (1.07, 0.81 to 1.40; 11 more per 1000, 38 fewer to 55 more; low certainty), when used alone, suggested an increase in the risk of death. Conclusion: These findings suggest that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumab, in combination with corticosteroids, might also reduce mortality. Tocilizumab and sarilumab, in combination with corticosteroids, could have similar effectiveness. Tocilizumab and sarilumab, when used alone, might not be beneficial.