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Objective(s): This study aimed to investigate the protective effects of fenugreek on CoCl2-induced hypoxia in neonatal rat cardiomyocytes.Materials and Methods: Primary cardiomyocytes were isolated from Sprague Dawley rats aged 0–2 days and incubated with various concentrations of fenugreek (10-320 µg/ml) and CoCl2-induced hypoxia for different durations (24, 48, and 72 hr). Cell viability, calcium signaling, beating rate, and gene expression were evaluated. Results: Fenugreek treatments did not cause any toxicity in cardiomyocytes. At a concentration of 160 µg/ml for 24 hr, fenugreek protected the heart against CoCl2-induced hypoxia, as evidenced by reduced expression of caspases (-3, -6, -8, and -9) and other functional genes markers, such as HIF-1α, Bcl-2, IP3R, ERK5, and GLP-1r. Calcium signaling and beating rate were also improved in fenugreek-treated cardiomyocytes. In contrast, CoCl2 treatment resulted in up-regulation of the hypoxia gene HIF-1α and apoptotic caspases gene (-3, -9, -8, -12), and down-regulation of Bcl-2 activity.Conclusion: Fenugreek treatment at a concentration of 160 µg/ml was not toxic to neonatal rat cardiomyocytes and protected against CoCl2-induced hypoxia. Furthermore, fenugreek improved calcium signaling and beating rate and altered gene expression. Fenugreek may be a potential therapeutic agent for promoting cardioprotection against hypoxia-induced injuries.

Sickle cell disease (SCD) is a complex genetic disorder associated with multiple clinical manifestations, including increased susceptibility to bacterial and viral infections. This review article presents a comprehensive analysis of the current literature obtained from various online databases focusing on the relationship between SCD and infections caused by specific pathogens, such as pneumonia- and influenza-causing pathogens, Escherichia coli, Staphylococcus aureus, parvovirus, and hepatitis viruses. We discuss the underlying mechanisms that contribute to the increased susceptibility of individuals with SCD to these infections, primarily related to the pathophysiology of variant hemoglobin (HbSS) and its impact on vascular occlusion, hemolysis, functional asplenia, and immune deficiency. Moreover, we highlight the significant burden of infections on SCD patients, particularly children under five years of age, where they are the leading cause of morbidity and mortality. Additionally, we address the challenges faced in attempts for reducing the global mortality rate associated with SCD, particularly in low-income countries, where factors such as increased pathogen exposure, co-morbidities like malnutrition, lower vaccination rates, and limited healthcare facilities contribute to the high disease burden. This review emphasizes the need for targeted interventions, improved healthcare access, vaccination programs, and infection prevention strategies to alleviate the impact of infections on individuals with SCD and reduce the global mortality rates associated with the disease.

Biohydrogen production from microalgae is a potential alternative energy source that is now intensively being researched. The complex natures of the biological processes involved have afflicted the accuracy of traditional modelling and optimization, besides being costly. Accordingly, machine learning algorithms have been employed to overcome setbacks, as these approaches have the capability to predict nonlinear interactions and handle multivariate data from microalgal biohydrogen studies. Thus, the review focuses on revealing the recent applications of machine learning techniques in microalgal biohydrogen production. The working principles of random forests, artificial neural networks, support vector machines, and regression algorithms are covered. The applications of these techniques are analyzed and compared for their effectiveness, advantages and disadvantages in the relationship studies, classification of results, and prediction of microalgal hydrogen production. These techniques have shown great performance despite limited data sets that are complex and nonlinear. However, the current techniques are still susceptible to overfitting, which could potentially reduce prediction performance. These could be potentially resolved or mitigated by comparing the methods, should the input data be limited.

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Pasupuleti VR, Prasad TNVKV, Sheikh RA, et al. Int J Nanomedicine. 2013;8(1):3355– 3364. At the authors request, the Editor and Publisher of International Journal of Nanomedicine wish to retract the published article. Concerns were raised over alleged image manipulation in Figure 5 in which elements of the image appeared to have duplicated several times. The authors responded to our queries but were unable to provide a satisfactory explanation for the alleged image manipulation. The authors were able to provide the original images for Figure 5 but they could not be used as a replacement for a corrigendum and both the Editor and authors agreed to retract the article. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Hepatotoxicity is a major global public health concern. Despite advances in modern medicine, the demerits of chemically prepared drugs outweigh their merits. In addition, the treatment of liver diseases based on modern medical principles has been found to produce several undesired side effects. Therefore, the exploration of medicinal plants has gained worldwide attention for treating various diseases, including liver diseases, owing to their potential efficacy and cost effectiveness. Several plants, including Andrographis paniculata, Bauhinia purpurea, Commelina nudiflora, Dillenia suffruticosa, Elaeis guineensis, Lygodium microphyllum, and Nephrolepis biserrata, have been reported with hepatoprotection. Moreover, these plants have been shown to play a vital role in ameliorating cellular damage because they contain several phytochemicals, including alkaloids, saponins, flavonoids, tannins, terpenoids, steroids, polyphenols, and diterpenoid lactones. The following antioxidant, anti-inflammatory, immunomodulatory, and hepatoprotective compounds have been found in these plants: andrographolide, rosmarinic acid, phenol, eugenol, 9,12-octadecadienoic, n-hexadecanoic acid, dihydroxy dimethoxy flavone, sitosterol, demethoxycurcumin, quercetin, linoleic acid, stigmasterol, kojic acid, indole-2-one, α-terpinol, linalool, kaempferol, catechin, ellagic acid, and oleanolic acid. This paper aimed to provide an in-depth review of in vivo studies on Malaysian medicinal plants possessing hepatoprotective properties, phytochemical ingredients, and antioxidant mechanisms, with an emphasis on the species proven particularly useful for treating hepatic disorders.

Abstract Background: The incidence and severity of Clostridium difficile infection (CDI) in patients with inflammatory bowel disease (IBD) is increasing. CDI is diagnosed by toxin enzyme immunoassay (EIA) or real-time polymerase chain reaction (PCR) performed on stool samples. An earlier study evaluating EIA in IBD patients with CDI suggested that more than one stool sample be tested to increase diagnostic yield. We investigated whether repeat stool testing improves diagnostic accuracy for CDI in hospitalized IBD patients compared to hospitalized patients with CDI and no IBD. Methods: We performed retrospective data analysis from January 2005-May 2011 on 63,086 hospitalized patients who were tested for CDI using EIA or PCR. Of these, 2579 patients had IBD. Transition probabilities were calculated based on results from repeated tests. Results: Inclusive of all inpatients tested for CDI, 56,583 were tested using toxin EIA and 6503 were tested using PCR. In patients with no IBD, the first stool sample tested was positive in 90% and 94% with EIA and PCR respectively. In IBD patients tested using EIA, 101 were diagnosed with CDI. The first stool sample tested was positive in 81% of patients. Successive second and third stool samples yielded additional 14% and 5% CDI positive IBD patients. Conclusions: Approximately one in five IBD patients with CDI required repeat testing to yield a positive result with EIA. There are minimal diagnostic gains of repeat testing by EIA or PCR in patients without IBD. We recommend repeat stool testing for CDI when using EIA to increase diagnostic yield in IBD patients. [ABSTRACT FROM AUTHOR]

Visweswara Rao Pasupuleti,1 TNVKV Prasad,2 Rayees Ahmad Shiekh,3 Satheesh Krishna Balam,4 Ganapathi Narasimhulu,5 Cirandur Suresh Reddy,4 Ismail Ab Rahman,3 Siew Hua Gan1 1Human Genome Center, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; 2Institute of Frontier Technology, Regional Agricultural Research Station, Acharya NG Ranga Agricultural University, Tirupati, Andhra Pradesh, India; 3Biomaterial Research Unit, School of Dental Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia; 4Department of Chemistry, Sri Venkateswara University, Tirupati, Andhra Pradesh, India; 5Pharmacology and Toxicology, Faculty of Pharmacy, University of Technology Mara, Malaysia Abstract: Nanotechnology is gaining momentum due to its ability to transform metals into nanoparticles. The synthesis, characterization, and applications of biologically synthesized nanomaterials have become an important branch of nanotechnology. Plant extracts are a cost-effective, ecologically friendly, and efficient alternative for the large-scale synthesis of nanoparticles. In this study, silver nanoparticles (AgNps) were synthesized using Rhinacanthus nasutus leaf extract. After exposing the silver ions to the leaf extract, the rapid reduction of silver ions led to the formation of AgNps in solution. The synthesis was confirmed by ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy, and transmission electron microscopy. The in vitro antimicrobial activity of the AgNps synthesized using R. nasutus leaf extract was investigated against Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Aspergillus niger, and Aspergillus flavus using a disc diffusion method. The AgNps showed potential activity against all of the bacterial strains and fungal colonies, indicating that R. nasutus has the potential to be used in the development of value-added products in the biomedical and nanotechnology-based industries. Keywords: R. nasutus, silver nanoparticles, TEM, antimicrobial activities

Background: Respiratory problems are usual in upper thoracic spinal cord injuries when compared to Lower thoracic spinal cord injuries. Generally there are frequent respiratory complications in the individuals with spinal cord injuries. The complications of the respiratory system are severe and more prevalent source of morbidity and mortality after the spinal cord injury due to the inefficient breathing capacity including inspiratory and expiratory abilities. The present study represents the inspiratory muscle training especially in upper thoracic spinal cord injury patients to assess the improvement in the pulmonary functions. Methods: Twenty five patients with the age between 25 -40 years with the upper spinal cord injuries were selected in the present study in order to assess the efficacy of the training. Several types of exercises were practiced including diaphragmatic breathing exercises, incentive spirometry, active cycle of breathing technique and weight training. COPD Conditions, Chest wall deformities, Hypertensive patients, Cardio vascular problems were excluded in the study. Results: The results from the study showed that significant changes were found in the patients treated with all the above mentioned techniques. Axillary level, nipple level, Xiphisternum levels were analysed and the results found to be significant after the treatment. Incentive spirometry and peak flow meter observations were also found to be significant when compare to the pretreatment. Conclusion: The present study conclude that the combined effect of incentive spriometry, diaphragmatic breathing exercises, and active cycle of breathing technique is more effective in improving the pulmonary functions in upper thoracic spinal cord injuries than single method efficiency.

Construction industry is the second most contributor of gross domestic product and the high rates of accidents /fatalities have tarnished the image of construction industry in India. The importance of safety at site cannot be underscored and it needs the combined attention of all stakeholders to address the issue of safety in construction industry in India. Although the construction industry plays an important role in contributing to the economic performance of the country, its contribution to the workplace accident is equally substantial. The unsatisfactory safety record of construction industry has always been highlighted since the safety management system is neglected area and has not been pursued and implemented systematically in the construction industry. Although the safety regulations imposed in the construction industry by Department of Labour through Building and other construction workers act, 1996 are quite comprehensive and most of the State Governments have not implemented the provisions mentioned under the act. Due to lack of enforcement from Government, majority of the construction organizations in India are certified under Occupational health safety assessment series (OHSAS 18001) to provide a safe and conducive working environment for their workers and subcontractors. The purpose of the study is to present a hierarchy decision model for assessing the priority of elements of goals of OHSAS 18001 in construction segments that is infrastructure and real estate in India by using the analytic hierarchy process(AHP) methodology.

Background: Guideline-recommended strategies to interrupt chronic anticoagulation with warfarin or direct oral anticoagulants (DOAC) during the perioperative period of cardiac implantable electronic device (CIED) surgery differ worldwide. There is uncertainty concerning the benefits and harms of interrupted and uninterrupted anticoagulation in patients undergoing CIED surgery., Objectives: To assess the benefits and harms of interrupted anticoagulation (IAC) with either warfarin or DOAC in the perioperative period of CIED surgery versus uninterrupted anticoagulation (UAC), with or without heparin bridging, during an equivalent time frame, for CIED surgery., Search Methods: CENTRAL, MEDLINE, Embase, Web of Science, and two trials registers were searched on 26 November 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. We plan to update this review imminently., Selection Criteria: We included randomized controlled trials (RCTs) evaluating IAC vs. UAC in adults with a diagnosed cardiac rhythm disorder, who underwent elective CIED surgery and received at least one month of warfarin or DOAC anticoagulation. Comparisons of interest were: (1) continued warfarin vs. interrupted warfarin anticoagulation, with or without heparin bridging; and (2) continued DOAC (apixaban, betrixaban, dabigatran, edoxaban, or rivaroxaban) vs. interrupted DOAC, with or without heparin bridging., Data Collection and Analysis: Primary outcomes were composite thromboembolic events (transient ischemic attack, ischemic stroke, deep vein thrombosis, pulmonary embolism, peripheral embolism, or valve thrombosis) and device-pocket hematoma. Secondary outcomes included individual components of composite thromboembolic events, composite bleeding events, all-cause mortality, adverse events, quality of life and days of hospitalization. Two authors independently selected studies, extracted data, and assessed the risk of bias. We assessed the certainty of evidence using GRADE. The inverse variance random-effects model was used for meta-analyses, and the DerSimonian and Laird method was used for calculating the between-study variance Tau 2 . Dichotomous outcomes were calculated as risk ratios (RRs) and we used mean differences (MDs) for continuous outcomes, with respective 95% confidence intervals (95% CIs)., Main Results: We identified 10 eligible studies (2221 participants), of which one is ongoing. Of these 10 studies, six compared IAC vs. UAC with warfarin (1267 participants) and four compared IAC vs. UAC with DOAC (954 participants). Follow-up duration ranged between 0.5 to three months. The mean age of participants ranged from 68 to 76 years. Definitions of thromboembolic events, device-pocket hematoma, and bleeding events varied across studies. IAC vs. UAC with warfarin IAC with warfarin may result in little to no difference in composite thromboembolic events (RR 0.85, 95% CI 0.18 to 4.11; 5 RCTs, n = 1266; low-certainty evidence). The evidence is very uncertain about the effect of IAC on device-pocket hematoma (RR 1.87, 95% CI 0.83 to 4.22; 5 RCTs, n = 1266; very low-certainty evidence), ischemic stroke (RR 0.70, 95% CI 0.11 to 4.40; 5 RCTs, n = 1266; very low-certainty evidence) and composite bleeding events (RR 1.92, 95% CI 0.84 to 4.43; 5 RCTs, very low-certainty evidence). IAC with warfarin likely results in little to no difference in deep vein thrombosis or pulmonary embolism (0 events in both groups; 2 RCTs, n = 782; moderate-certainty evidence). IAC may result in a slight reduction of all-cause mortality (RR 0.35, 95% CI 0.04 to 2.93; 3 RCTs, n = 953; low-certainty evidence). IAC vs. UAC with DOAC IAC with DOAC may result in little to no difference in composite thromboembolic events (RR 0.98, 95% CI 0.06 to 15.63; 3 RCTs, n = 843; low-certainty evidence) and ischemic stroke (RR 0.98, 95% CI 0.06 to 15.63, 2 RCTs, n = 763; low-certainty evidence). The evidence is very uncertain about the effect of IAC with DOAC on device-pocket hematoma (RR 1.07, 95% CI 0.55 to 2.11; 4 RCTs, n = 954; very low-certainty evidence) and composite bleeding events (RR 1.07, 95% CI 0.55 to 2.06; 4 RCTs, n = 954; very low-certainty evidence). IAC may result in little to no difference in ischemic stroke (RR 0.98, 95% CI 0.06 to 15.63, 2 RCTs, low-certainty evidence). IAC likely results in little to no difference in deep vein thrombosis or pulmonary embolism (0 events in both groups; 2 RCTs, n = 763; moderate-certainty evidence). IAC may result in a slight reduction of all-cause mortality (RR 0.49, 95% CI 0.04 to 5.39; 2 RCTs, n = 763; low-certainty evidence)., Authors' Conclusions: Interrupted anticoagulation in people undergoing elective CIED surgery had similar outcomes to uninterrupted anticoagulation with either warfarin or DOAC medications. Certainty of evidence was judged to be low to very low for most of the assessed outcomes. Further RCTs are particularly needed to help identify whether IAC significantly impacts the risks of thromboembolic events and device-pocket hematoma., (Copyright © 2025 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Introduction: We systematically assessed benefits and harms of the use of ivermectin in non-hospitalized patients with early COVID-19., Methods: Five databases were searched until October 17, 2023, for randomized controlled trials (RCTs) in adult patients with COVID-19 treated with ivermectin against standard of care (SoC), placebo, or active drug. Primary outcomes were hospitalization, all-cause mortality, and adverse events (AEs). Secondary outcomes included mechanical ventilation (MV), clinical improvement, clinical worsening, viral clearance, and severe adverse events (SAEs). Random effects meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods. Pre-specified subgroup analyses (ivermectin dose, control type, risk of bias, follow-up, and country income) and trial sequential analysis (TSA) were performed., Results: Twelve RCTs (n = 7,035) were included. The controls were placebo in nine RCTs, SoC in two RCTs, and placebo or active drug in one RCT. Ivermectin did not reduce hospitalization (relative risk [RR], 0.81, 95% confidence interval [95% CI] 0.64-1.03; 8 RCTs, low QoE), all-cause mortality (RR 0.98, 95% CI 0.73-1.33; 9 RCTs, low QoE), or AEs (RR 0.89, 95% CI 0.75-1.07; 9 RCTs, very low QoE) vs. controls. Ivermectin did not reduce MV, clinical worsening, or SAEs and did not increase clinical improvement and viral clearance vs. controls (very low QoE for secondary outcomes). Subgroup analyses were mostly consistent with main analyses, and TSA-adjusted risk for hospitalization was similar to main analysis., Conclusions: In non-hospitalized COVID-19 patients, ivermectin did not have effect on clinical, non-clinical or safety outcomes versus controls. Ivermectin should not be recommended as treatment in non-hospitalized COVID-19 patients., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: Palbociclib in combination with endocrine therapy is approved for treatment of hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. In addition to clinical trials, several real-world studies have evaluated the effectiveness of palbociclib. With increased life expectancy in the general population, breast cancer in older women is also expected to increase., Objective: The aim was to systematically review evidence from both clinical trials and real-world studies for palbociclib treatment outcomes in older patients with HR+/HER2- advanced/metastatic breast cancer (a/mBC). Older patients are often underrepresented in clinical trials, and real-world evidence (RWE) will enrich the analysis of palbociclib outcomes in this subgroup of patients., Design: A systematic literature search in PubMed, EMBASE, and Cochrane Library through May 4, 2023, yielded 2355 unique articles. A total of 52 articles (13 and 39 articles reporting results from seven randomized controlled trials [RCTs] and 37 RWE studies, respectively) were included based on study eligibility criteria., Results: All RCTs used age cutoffs of ≥ 65 years to define older population (n = 722; 437 received palbociclib); all RWE studies, except one with an age cutoff of > 60 years, had age cutoffs of ≥ 65 years or higher to define older population (n = 9840; 7408 received palbociclib). Overall, in studies that compared efficacy (progression-free survival [seven RCTs, 20 RWE studies], overall survival [four RCTs, 11 RWE studies], tumor response [three RWE studies], and clinical benefit rate [one RCT, two RWE studies]) and safety outcomes (three RCTs, three RWE studies) between older and younger patients, palbociclib showed similar benefits, regardless of age. Results from two RCTs and two RWE studies showed that global quality of life (QoL) was maintained in older patients receiving palbociclib. Overall, palbociclib dose modifications (two RWE studies), dose reductions (one RCT, seven RWE studies), and treatment discontinuation rates (three RCTs, three RWE studies) were higher in older patients compared with younger patients; however, these differences did not appear to adversely impact efficacy outcomes., Conclusions: In this systematic review, data from RCTs showed that palbociclib was effective, well tolerated, and maintained QoL in older patients with HR+/HER2- a/mBC. Palbociclib treatment in older patients in real-world settings was associated with similar clinical benefit as in RCTs., Prospero Registration: CRD42023444195., (© 2024. The Author(s).)

Glioblastoma multiforme is a highly malignant brain tumor with significant intra- and intertumoral heterogeneity known for its aggressive nature and poor prognosis. The complex signaling cascade that regulates this heterogeneity makes targeted drug therapy ineffective. The development of an optimal preclinical model is crucial for the comprehension of molecular heterogeneity and enhancing therapeutic efficacy. The ideal model should establish a relationship between various oncogenes and their corresponding responses. This review presents an analysis of preclinical in vivo and in vitro models that have contributed to the advancement of knowledge in model development. The experimental designs utilized in vivo models consisting of both immunodeficient and immunocompetent mice induced with intracranial glioma. The transgenic model was generated using various techniques, like the viral vector delivery system, transposon system, Cre-LoxP model, and CRISPR-Cas9 approaches. The utilization of the patient-derived xenograft model in glioma research is valuable because it closely replicates the human glioma microenvironment, providing evidence of tumor heterogeneity. The utilization of in vitro techniques in the initial stages of research facilitated the comprehension of molecular interactions. However, these techniques are inadequate in reproducing the interactions between cells and extracellular matrix (ECM). As a result, bioengineered 3D-in vitro models, including spheroids, scaffolds, and brain organoids, were developed to cultivate glioma cells in a three-dimensional environment. These models have enabled researchers to understand the influence of ECM on the invasive nature of tumors. Collectively, these preclinical models effectively depict the molecular pathways and facilitate the evaluation of multiple molecules while tailoring drug therapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Monoclonal antibody Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors reduce total cholesterol (TC), low density lipoproteins (LDL), high density lipoproteins (HDL), and triglycerides (TG). We assessed the ability of berberine, a natural PCSK9 inhibitor, to reduce lipid concentrations either alone or combined with other nutraceuticals. We searched PubMed, Scopus and EMBASE from inception to September 30 th , 2022 for randomized controlled trials (RCTs) assessing 8-18 wk of berberine therapy on. A total of 41 RCTs with 4,838 patients met our inclusion criteria. Berberine containing products significantly reduced TC (MD -17.42 mg/dL [95%CI: -22.91 to -11.93]), LDL (MD -14.98 mg/dL [95%CI: -20.67 to -9.28]), and TG (MD -18.67 mg/dL [95%CI: -25.82 to -11.51]) while raising HDL (MD 1.97 mg/dL [95%CI: 1.16 to 2.78]) versus control (I 2 > 72% for all analyses). Products with berberine alone had less robust effects on TC (MD -12.08 mg/dL [95%CI: -21.79 to -2.37]), LDL (MD -9.26 mg/dL [95%CI: -20.31 to 1.78]), and HDL (MD 1.38 mg/dL [95%CI: -1.27 to 4.03]) but TG effects were similar (MD -17.40 mg/dL [95%CI: -32.57 to -2.23]). Berberine along with red yeast rice reduced TC (MD -19.62 mg/dL [95%CI: -28.56 to -10.68]) and LDL (MD -18.79 mg/dL [95%CI: -28.03 to -9.54]) as did combination therapy with Silybum maranium for TC (MD -31.81 mg/dL [95%CI: -59.88 to -3.73]) and LDL (MD -30.82 mg/dL [95%CI: -56.48 to -5.16]). Berberine, alone or with other nutraceuticals, can provide a modest positive impact on lipid concentrations.

Introduction: Heart failure (HF) is still a major cause of morbidity and mortality all over the world. Aim of the study was to assess the benefits and harms of sacubitril/valsartan (S/V) compared to angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in patients with HF., Material and Methods: We systematically searched for randomised controlled trials (RCTs) evaluating S/V vs. ACEI or ARB in acute or chronic HF in August 2021. Primary outcomes were HF hospitalisations and cardiovascular (CV) mortality; secondary outcomes included all-cause mortality, biomarkers, and renal function., Results: We selected 11 RCTs ( n = 18766) with 2-48 months follow-up. Five RCTs had ACEIs as control, 5 RCTs had ARBs as control, and one RCT had both ACEI and ARB as control. Compared to ACEI or ARB, S/V reduced HF hospitalisations by 20% (HR = 0.80, 95% CI: 0.68-0.94; 3 RCTs; I 2 = 65%; high CoE), CV mortality by 14% (HR = 0.86, 95% CI: 0.73-1.01; 2 RCTs; I 2 = 57%; high CoE), and all-cause mortality by 11% (HR = 0.89, 95% CI: 0.78-1.00; 3 RCTs; I 2 = 36%; high CoE). S/V reduced NTproBNP (SMD = -0.34, 95% CI: -0.52 to -0.16; 3 RCTs; I 2 = 62%) and hs-TNT (ratio of differences = 0.84, 95% CI: 0.79-0.88; 2 RCTs; I 2 = 0%), and caused a decline in renal function by 33% (HR = 0.67, 95% CI: 0.39-1.14; 2 RCTs; I 2 = 78%; high CoE). S/V increased hypotension (RR = 1.69, 95% CI: 1.33-2.15; 9 RCTs; I 2 = 65%; high CoE). Hyperkalaemia and angioedema events were similar. Effects were in the same direction when stratified by type of control (ACEI vs. ARB)., Conclusions: Sacubitril/valsartan had better clinical, intermediate, and renal outcomes in HF in comparison to ACEI or ARB. There was no difference in angioedema and hyperkalaemia events, but there were more hypotension events., Competing Interests: M.B. has received research grants/support from Amgen, Mylan/Viatris, Sanofi, and Valeant, and he has served as a consultant/received speakers fee from Amgen, Daiichi-Sankyo, Esperion, Freia Pharmaceuticals, Herbapol, Kogen, KRKA, Mylan/Viatris, Novartis, Novo-Nordisk, Polfarmex, Polpharma, Sanofi-Aventis, Servier, Teva, and Zentiva. He is CMO at the Nomi Biotech Corporation Ltd. A.M.B.-D. has given lectures that were sponsored by Novartis Polska Sp.z o. o. The remaining authors do not have any competing interests to disclose., (Copyright: © 2023 Termedia & Banach.)

Objective: We systematically assessed the efficacy of tunnel technique (TUN) vs. coronally advanced flap (CAF) in the management of multiple gingival recession defects in adults., Methods: Five databases were searched until September 2021 for randomized controlled trials (RCTs) assessing TUN vs. CAF; grafts of interest were acellular dermal matrix (ADM) and connective tissue graft (CTG). Primary outcomes were root coverage (RC) and complete root coverage (CRC). Secondary outcomes were clinical attachment level (CAL), keratinized tissue width (KTW), probing depth (PD), and recession coverage (REC). Effect measures were risk ratio (RR) or mean difference (MD) with their confidence intervals (95% CI). Inverse variance methods and random-effects model meta-analyses were used. Subgroup analyses by the type of graft were performed. Quality of evidence was assessed using GRADE methodology., Results: Five RCTs ( n  = 173) were included, with a follow-up of 6 months for all outcomes. In comparison to CAF, TUN did not significantly reduce CRC (RR 0.65; 95% CI 0.002-176.7; p = 0.51) and did not increase RC (MD 0.99%; 95% CI -6.7 to 8.6; p = 0.80). In comparison to CAF, TUN showed no significant reduction of secondary outcomes. Subgroup analyses by type of graft showed no differences in comparison to primary analyses for primary and secondary outcomes. Three RCTs had a high risk of bias, and five RCTs had very low quality of evidence for all outcomes., Conclusions: In adults with gingival recessions, TUN had similar primary and secondary outcomes in comparison with CAF. Subgroup analyses by the type of graft did not affect main conclusions. More RCTs with better design are needed to further characterize the effects of TUN vs. CAF in the treatment of multiple gingival recession defects., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Frank Mayta-Tovalino et al.)

Background: We systematically assessed beneficial and harmful effects of monoclonal antibodies for coronavirus disease 2019 (COVID-19) treatment, and prophylaxis in individuals exposed to severe acute respiratory syndrome coronavirus 2., Methods: We searched 5 engines and 3 registries until November 3, 2021 for randomized controlled trials evaluating monoclonal antibodies vs control in hospitalized or non-hospitalized adults with COVID-19, or as prophylaxis. Primary outcomes were all-cause mortality, COVID-19-related death, and serious adverse events; hospitalization for non-hospitalized; and development of symptomatic COVID-19 for prophylaxis. Inverse variance random effects models were used for meta-analyses. Grading of Recommendations, Assessment, Development, and Evaluations methodology was used to assess certainty of evidence., Results: Twenty-seven randomized controlled trials were included: 20 in hospitalized patients (n = 8253), 5 in non-hospitalized patients (n = 2922), and 2 in prophylaxis (n = 2680). In hospitalized patients, monoclonal antibodies slightly reduced mechanical ventilation (relative risk [RR] 0.74; 95% confidence interval [CI], 0.60-0.9; I 2  = 20%, low certainty of evidence) and bacteremia (RR 0.77; 95% CI, 0.64-0.92; I 2  = 7%, low certainty of evidence); evidence was very uncertain about the effect on adverse events (RR 1.31; 95% CI, 1.02-1.67; I 2  = 77%, very low certainty of evidence). In non-hospitalized patients, monoclonal antibodies reduced hospitalizations (RR 0.30; 95% CI, 0.17-0.53; I 2  = 0%, high certainty of evidence) and may slightly reduce serious adverse events (RR 0.47; 95% CI, 0.22-1.01; I 2  = 33%, low certainty of evidence). In prophylaxis studies, monoclonal antibodies probably reduced viral load slightly (mean difference -0.8 log 10 ; 95% CI, -1.21 to -0.39, moderate certainty of evidence). There were no effects on other outcomes., Conclusions: Monoclonal antibodies had limited effects on most of the outcomes in COVID-19 patients, and when used as prophylaxis. Additional data are needed to determine their efficacy and safety., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In consideration of the emergence of novel drug-resistant microbial strains and the increase in the incidences of various cancers throughout the world, honey could be utilized as a great alternative source of potent bioactive compounds. In this context, this study pioneers in reporting the phytochemical profiling and the antimicrobial, antioxidant, and anticancer properties of Acacia honey (AH) from the Hail region of Saudi Arabia, assessed using in vitro and molecular docking approaches. The phytochemical profiling based on high-resolution liquid chromatography-mass spectrometry (HR-LCMS) revealed eight compounds and three small peptide-like proteins as the constituents. The honey samples exhibited promising antioxidant activities (DPPH-IC 50  = 0.670 mg/mL; ABTS-IC 50  = 1.056 mg/mL; β -carotene-IC 50  > 5 mg/mL). In the well-diffusion assay, a high mean growth inhibition zone (mGIZ) was observed against Staphylococcus aureus (48.33 ± 1.53 mm), Escherichia coli ATCC 10536 (38.33 ± 1.53 mm), and Staphylococcus epidermidis ATCC 12228 (39.33 ± 1.15 mm). The microdilution assay revealed that low concentrations of AH could inhibit the growth of almost all the evaluated bacterial and fungal strains, with the minimal bactericidal concentration values (MBCs) ranging from 75 mg/mL to 300 mg/mL. On the contrary, high AH concentrations were required to kill the tested microorganisms, with the minimal bactericidal concentration values (MBCs) ranging from approximately 300 mg/mL to over 600 mg/mL and the minimal fungicidal concentration values (MFCs) of approximately 600 mg/mL. The AH exhibited effective anticancer activity in a dose-dependent manner against breast (MCF-7), colon (HCT-116), and lung (A549) cancer cell lines, with the corresponding IC 50 values of 5.053  μ g/mL, 5.382  μ g/mL, and 6.728  μ g/mL, respectively. The in silico investigation revealed that the observed antimicrobial, antioxidant, and anticancer activities of the constituent compounds of AH are thermodynamically feasible, particularly those of the tripeptides (Asp-Trp-His and Trp-Arg-Ala) and aminocyclitol glycoside. The overall results highlighted the potential of AH as a source of bioactive compounds with significant antimicrobial, antioxidant, and anticancer activities, which could imply further pharmacological applications of AH., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Walid Sabri Hamadou et al.)

Introduction: We systematically assessed benefits and harms of tocilizumab (TCZ), which is an antibody blocking IL-6 receptors, in hospitalized COVID-19 patients., Methods: Five electronic databases and two preprint webpages were searched until March 4, 2021. Randomized controlled trials (RCTs) and inverse probability treatment weighting (IPTW) cohorts assessing TCZ effects in hospitalized, COVID-19 adult patients were included. Primary outcomes were all-cause mortality, clinical worsening, clinical improvement, need for mechanical ventilation, and adverse events (AE). Inverse variance random-effects meta-analyses were performed with quality of evidence (QoE) evaluated using GRADE methodology., Results: Nine RCTs (n = 7,021) and nine IPTW cohorts (n = 7,796) were included. TCZ significantly reduced all-cause mortality in RCTs (RR 0.89, 95%CI 0.81-0.98, p = 0.03; moderate QoE) and non-significantly in cohorts (RR 0.67, 95%CI 0.44-1.02, p = 0.08; very low QoE) vs. control (standard of care [SOC] or placebo). TCZ significantly reduced the need for mechanical ventilation (RR 0.80, 95%CI 0.71-0.90, p = 0.001; moderate QoE) and length of stay (MD -1.92 days, 95%CI -3.46 to -0.38, p = 0.01; low QoE) vs. control in RCTs. There was no significant difference in clinical improvement or worsening between treatments. AEs, severe AEs, bleeding and thrombotic events were similar between arms in RCTs, but there was higher neutropenia risk with TCZ (very low QoE). Subgroup analyses by disease severity or risk of bias (RoB) were consistent with main analyses. Quality of evidence was moderate to very low in both RCTs and cohorts., Conclusions: In comparison to SOC or placebo, TCZ reduced all-cause mortality in all studies and reduced mechanical ventilation and length of stay in RCTs in hospitalized COVID-19 patients. Other clinical outcomes were not significantly impacted. TCZ did not have effect on AEs, except a significant increased neutropenia risk in RCTs. TCZ has a potential role in the treatment of hospitalized COVID-19 patients., Competing Interests: The authors have declared that no competing interests exist.

Background: We systematically assessed benefits and harms of the use of ivermectin (IVM) in patients with coronavirus disease 2019 (COVID-19)., Methods: Published and preprint randomized controlled trials (RCTs) assessing the effects of IVM on adult patients with COVID-19 were searched until 22 March 2021 in 5 engines. Primary outcomes were all-cause mortality rate, length of hospital stay (LOS), and adverse events (AEs). Secondary outcomes included viral clearance and severe AEs (SAEs). The risk of bias (RoB) was evaluated using the Cochrane Risk of Bias 2.0 tool. Inverse variance random effect meta-analyses were performed, with quality of evidence (QoE) evaluated using GRADE methods., Results: Ten RCTs (n = 1173) were included. The controls were the standard of care in 5 RCTs and placebo in 5. COVID-19 disease severity was mild in 8 RCTs, moderate in 1, and mild and moderate in 1. IVM did not reduce all-cause mortality rates compared with controls (relative risk [RR], 0.37 [95% confidence interval, .12-1.13]; very low QoE) or LOS compared with controls (mean difference, 0.72 days [95% confidence interval, -.86 to 2.29 days]; very low QoE). AEs, SAEs, and viral clearance were similar between IVM and control groups (low QoE for all outcomes). Subgroups by severity of COVID-19 or RoB were mostly consistent with main analyses; all-cause mortality rates in 3 RCTs at high RoB were reduced with IVM., Conclusions: Compared with the standard of care or placebo, IVM did not reduce all-cause mortality, LOS, or viral clearance in RCTs in patients with mostly mild COVID-19. IVM did not have an effect on AEs or SAEs and is not a viable option to treat patients with COVID-19., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: Angiogenic factor AGGF1 (angiogenic factor with G-patch and FHA [Forkhead-associated] domain 1) promotes angiogenesis as potently as VEGFA (vascular endothelial growth factor A) and regulates endothelial cell (EC) proliferation, migration, specification of multipotent hemangioblasts and venous ECs, hematopoiesis, and vascular development and causes vascular disease Klippel-Trenaunay syndrome when mutated. However, the receptor for AGGF1 and the underlying molecular mechanisms remain to be defined., Approach and Results: Using functional blocking studies with neutralizing antibodies, we identified [alpha]5[beta]1 as the receptor for AGGF1 on ECs. AGGF1 interacts with [alpha]5[beta]1 and activates FAK (focal adhesion kinase), Src (proto-oncogene tyrosine-protein kinase), and AKT (protein kinase B). Functional analysis of 12 serial N-terminal deletions and 13 C-terminal deletions by every 50 amino acids mapped the angiogenic domain of AGGF1 to a domain between amino acids 604-613 (FQRDDAPAS). The angiogenic domain is required for EC adhesion and migration, capillary tube formation, and AKT activation. The deletion of the angiogenic domain eliminated the effects of AGGF1 on therapeutic angiogenesis and increased blood flow in a mouse model for peripheral artery disease. A 40-mer or 15-mer peptide containing the angiogenic domain blocks AGGF1 function, however, a 15-mer peptide containing a single amino acid mutation from -RDD- to -RGD- (a classical RGD integrin-binding motif) failed to block AGGF1 function., Conclusions: We have identified integrin [alpha]5[beta]1 as an EC receptor for AGGF1 and a novel AGGF1-mediated signaling pathway of [alpha]5[beta]1-FAK-Src-AKT for angiogenesis. Our results identify an FQRDDAPAS angiogenic domain of AGGF1 crucial for its interaction with [alpha]5[beta]1 and signaling.

Introduction: No early treatment intervention for COVID-19 has proven effective to date. We systematically reviewed the efficacy of hydroxychloroquine as early treatment for COVID-19., Material and Methods: Randomized controlled trials (RCTs) evaluating hydroxychloroquine for early treatment of COVID-19 were searched in five engines and preprint websites until September 14, 2021. Primary outcomes were hospitalization and all-cause mortality. Secondary outcomes included COVID-19 symptom resolution, viral clearance, and adverse events. Inverse variance random-effects meta-analyses were performed and quality of evidence (QoE) per outcome was assessed with GRADE methods., Results: Five RCTs ( n = 1848) were included. The comparator was placebo in four RCTs and usual care in one RCT. The RCTs used hydroxychloroquine total doses between 1,600 and 4,400 mg and had follow-up times between 14 and 90 days. Compared to the controls, early treatment with hydroxychloroquine did not reduce hospitalizations (RR = 0.80, 95% CI: 0.47-1.36, I 2 = 2%, 5 RCTs, low QoE), all-cause mortality (RR = 0.77, 95% CI: 0.16-3.68, I 2 = 0%, 5 RCTs, very low QoE), symptom resolution (RR = 0.94, 95% CI: 0.77-1.16, I 2 = 71%, 3 RCTs, low QoE) or viral clearance at 14 days (RR = 1.02, 95% CI: 0.82-1.27, I 2 = 65%, 2 RCTs, low QoE). There was a larger non-significant increase of adverse events with hydroxychloroquine vs. controls (RR = 2.17, 95% CI: 0.86-5.45, I 2 = 92%, 5 RCTs, very low QoE)., Conclusions: Hydroxychloroquine was not efficacious as early treatment for COVID-19 infections in RCTs with low to very low quality of evidence for all outcomes. More RCTs are needed to elucidate the efficacy of hydroxychloroquine as early treatment intervention., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 Termedia & Banach.)

There are no proven prophylactic interventions for COVID-19. We systematically reviewed the efficacy of prophylactic hydroxychloroquine for COVID-19. Studies evaluating hydroxychloroquine for prophylaxis of COVID-19 were searched in several engines until 8 December 2020. Primary outcomes included RT-PCR positivity, COVID-19 infections (positive RT-PCR or compatible COVID-19 symptoms), and all-cause mortality. Random effects meta-analyses were performed for all outcomes. Five randomized controlled trials (RCTs) ( n = 5579) and one cohort ( n = 106) were included. Placebo was the comparator in four RCTs, and usual care in one RCT. Compared to the controls, five RCTs showed that hydroxychloroquine prophylaxis did not reduce RT-PCR positivity (RR 1.01, 95% CI 0.88-1.16), COVID-19 infection (RR 0.98, 95% CI 0.78-1.22), or all-cause mortality (RR 0.73, 95% CI 0.27-1.99). There were no differences of effects by pre- or post-exposure prophylaxis. Prophylaxis with hydroxychloroquine increased the risk of diarrhea, abdominal pain, or vomiting (RR 4.56, 95% CI 1.58-13.19). There were no effects of hydroxychloroquine on other secondary outcomes. Quality of evidence was low to very low for all outcomes. Hydroxychloroquine was not efficacious as a prophylaxis for COVID-19 infections, defined either as RT-PCR positivity or as a composite of RT-PCR positivity or compatible symptoms. Hydroxychloroquine did not reduce all-cause mortality, clinical worsening, or adverse events.

Background: Inflammation plays a key role in atherosclerotic plaque destabilization and adverse cardiac remodeling. Recent evidence has shown a promising role of colchicine in patients with coronary artery disease. We evaluated the efficacy and safety of colchicine in post-acute myocardial infarction (MI) patients. Methods: We searched five electronic databases from inception to January 18, 2021, for randomized controlled trials (RCTs) evaluating colchicine in post-acute MI patients. Primary outcomes were cardiovascular mortality and recurrent MI. Secondary outcomes were all-cause mortality, stroke, urgent coronary revascularization, levels of follow-up high-sensitivity C-reactive protein (hs-CRP), and drug-related adverse events. All meta-analyses used inverse-variance random-effects models. Results: Six RCTs involving 6,005 patients were included. Colchicine did not significantly reduce cardiovascular mortality [risk ratio (RR), 0.91; 95% confidence interval (95% CI), 0.52-1.61; p = 0.64], recurrent MI (RR, 0.87; 95% CI, 0.62-1.22; p = 0.28), all-cause mortality (RR, 1.06; 95% CI, 0.61-1.85; p = 0.78), stroke (RR, 0.28; 95% CI, 0.07-1.09; p = 0.05), urgent coronary revascularization (RR, 0.46; 95% CI, 0.02-8.89; p = 0.19), or decreased levels of follow-up hs-CRP (mean difference, -1.95 mg/L; 95% CI, -12.88 to 8.98; p = 0.61) compared to the control group. There was no increase in any adverse events (RR, 0.97; 95% CI, 0.89-1.07; p = 0.34) or gastrointestinal adverse events (RR, 2.49; 95% CI, 0.48-12.99; p = 0.20). Subgroup analyses by colchicine dose (0.5 vs. 1 mg/day), time of follow-up (<1 vs. ≥1 year), and treatment duration (≤30 vs. >30 days) showed no changes in the overall findings. Conclusion: In post-acute MI patients, colchicine does not reduce cardiovascular or all-cause mortality, recurrent MI, or other cardiovascular outcomes. Also, colchicine did not increase drug-related adverse events., Competing Interests: VP was employed by the company MedErgy HealthGroup, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Diaz-Arocutipa, Benites-Meza, Chambergo-Michilot, Barboza, Pasupuleti, Bueno, Sambola and Hernandez.)

We systematically reviewed the efficacy and safety of hydroxychloroquine as treatment for hospitalized COVID-19. Randomized controlled trials (RCTs) evaluating hydroxychloroquine as treatment for hospitalized COVID-19 patients were searched until 2nd of December 2020. Primary outcomes were all-cause mortality, need of mechanical ventilation, need of non-invasive ventilation, ICU admission and oxygen support at 14 and 30 days. Secondary outcomes were clinical recovery and worsening, discharge, radiological progression of pneumonia, virologic clearance, serious adverse events (SAE) and adverse events. Inverse variance random effects meta-analyses were performed. Thirteen RCTs ( n =18,540) were included. Hydroxychloroquine total doses ranged between 2000 and 12,400 mg; treatment durations were from 5 to 16 days and follow up times between 5 and 30 days. Compared to controls, hydroxychloroquine non-significantly increased mortality at 14 days (RR 1.07, 95%CI 0.92-1.25) or 30 days (RR 1.08, 95%CI 1.00-1.16). Hydroxychloroquine did not affect other primary or secondary outcomes, except SAEs that were significantly higher than the control (RR 1.24, 95%CI 1.05-1.46). Eleven RCTs had high or some concerns of bias. Subgroup analyses were consistent with main analyses. Hydroxychloroquine was not efficacious for treating hospitalized COVID-19 patients and caused more severe adverse events. Hydroxychloroquine should not be recommended as treatment for hospitalized COVID-19 patients.

Introduction: We systematically reviewed benefits and harms of convalescent plasma (CP) in hospitalized COVID-19 patients., Material and Methods: Randomized controlled trials (RCTs) and observational studies assessing CP effects on hospitalized, adult COVID-19 patients were searched until November 24, 2020. We assessed risk of bias (RoB) using Cochrane RoB 2.0 and ROBINS-I tools. Inverse variance random effect meta-analyses were performed. Quality of evidence was evaluated using GRADE methodology. Primary outcomes were all-cause mortality, clinical improvement, and adverse events., Results: Five RCTs ( n = 1067) and 6 cohorts ( n = 881) were included. Three and 1 RCTs had some concerns and high RoB, respectively; and there was serious RoB in all cohorts. Convalescent plasma did not reduce all-cause mortality in RCTs of severe (RR = 0.60, 95% CI: 0.33-1.10) or moderate (RR = 0.60, 95% CI: 0.09-3.86) COVID-19 vs. standard of care (SOC); CP reduced all-cause mortality vs. SOC in cohorts (RR = 0.66, 95% CI: 0.49-0.91). Convalescent plasma did not reduce invasive ventilation vs. SOC in moderate disease (RR = 0.85, 95% CI: 0.47-1.55). In comparison to placebo + SOC, CP did not affect all-cause mortality (RR = 0.75, 95% CI: 0.48-1.16) or clinical improvement (HR = 1.07, 95% CI: 0.82-1.40) in severe patients. Adverse and serious adverse events were scarce, similar between CP and controls. Quality of evidence was low or very low for most outcomes., Conclusions: In comparison to SOC or placebo + SOC, CP did not reduce all-cause mortality in RCTs of hospitalized COVID-19 patients. Convalescent plasma did not have an effect on other clinical or safety outcomes. Until now there is no good quality evidence to recommend CP for hospitalized COVID-19 patients., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Termedia & Banach.)

Comparative efficacy and safety of renal denervation (RDN) interventions for uncontrolled (UH) and resistant hypertension (RH) is unknown. We assessed the comparative efficacy and safety of existing RDN interventions for UH and RH. Six search engines were searched up to 1 May 2020. Primary outcomes were mean 24-h ambulatory and office systolic blood pressure (SBP). Secondary outcomes were mean 24-h ambulatory and office diastolic blood pressure (DBP), clinical outcomes, and serious adverse events. Frequentist random-effects network meta-analyses were used to evaluate effects of RDN interventions. Twenty randomized controlled trials (RCTs) ( n = 2152) were included, 15 in RH ( n = 1544) and five in UH ( n = 608). Intervention arms included radiofrequency (RF) in main renal artery (MRA) ( n = 10), RF in MRA and branches ( n = 4), RF in MRA+ antihypertensive therapy (AHT) ( n = 5), ultrasound (US) in MRA ( n = 3), sham ( n = 8), and AHT ( n = 9). RF in MRA and branches ranked as the best treatment to reduce 24-h ambulatory, daytime, and nighttime SBP and DBP versus other interventions (p-scores: 0.83 to 0.97); significant blood pressure effects were found versus sham or AHT. RF in MRA+AHT was the best treatment to reduce office SBP and DBP (p-scores: 0.84 and 0.90, respectively). RF in MRA and branches was the most efficacious versus other interventions to reduce 24-h ambulatory SBP and DBP in UH or RH.

Background: To systematically evaluate short-term efficacy of UCM versus other interventions in preterm infants., Methods: Six engines were searched until February 2020 for randomized controlled trials (RCTs) assessing UCM versus immediate cord clamping (ICC), delayed cord clamping (DCC), or no intervention. Primary outcomes were overall mortality, intraventricular hemorrhage (IVH), and patent ductus arteriosus (PDA); secondary outcomes were need for blood transfusion, mean blood pressure (MBP), serum hemoglobin (Hb), and ferritin levels. Random-effects meta-analyses were used., Results: Fourteen RCTs (n = 1708) were included. In comparison to ICC, UCM did not decrease mortality (RR 0.5, 95% CI 0.2-1.1), IVH (RR 0.7, 95% CI 0.5-1.0), or PDA (RR 1.0, 95% CI 0.7-1.5). However, UCM reduced need of blood transfusion (RR 0.5, 95% CI 0.3-0.9) and increased MBP (MD 2.5 mm Hg, 95% CI 0.5-4.5), Hb (MD 1.2 g/dL, 95% CI 0.8-1.6), and ferritin (MD 151.4 ng/dL, 95% CI 59.5-243.3). In comparison to DCC, UCM did not reduce mortality, IVH, PDA, or need of blood transfusion but increased MBP (MD 3.7, 95% CI 0.6-6.9) and Hb (MD 0.3, 95% CI -0.2-0.8). Only two RCTs had high risk of bias., Conclusions: UCM did not decrease short-term clinical outcomes in comparison to ICC or DCC in preterm infants. Intermediate outcomes improved significantly with UCM., Impact: In 14 randomized controlled trials (RCTs), umbilical cord milking (UCM) did not reduce mortality, intraventricular hemorrhage, or patent ductus arteriosus compared to immediate (ICC) or delayed cord clamping (DCC). UCM improved mean blood pressure and hemoglobin levels compared to ICC or DCC. In comparison to ICC, UCM reduced the need for blood transfusion. We updated searches until February 2020, stratified by type of control, and performed subgroup analyses. There was low quality of evidence about clinical efficacy of UCM. Most of RCTs had low risk of bias. UCM cannot be recommended as standard of care for preterm infants.

Background: Efficacy and safety of treatments for hospitalized COVID-19 are uncertain. We systematically reviewed efficacy and safety of remdesivir for the treatment of COVID-19., Methods: Studies evaluating remdesivir in adults with hospitalized COVID-19 were searched in several engines until August 21, 2020. Primary outcomes included all-cause mortality, clinical improvement or recovery, need for invasive ventilation, and serious adverse events (SAEs). Inverse variance random effects meta-analyses were performed., Results: We included four randomized controlled trials (RCTs) (n = 2296) [two vs. placebo (n = 1299) and two comparing 5-day vs. 10-day regimens (n = 997)], and two case series (n = 88). Studies used intravenous remdesivir 200mg the first day and 100mg for four or nine more days. One RCT (n = 236) was stopped early due to AEs; the other three RCTs reported outcomes between 11 and 15 days. Time to recovery was decreased by 4 days with remdesivir vs. placebo in one RCT (n = 1063), and by 0.8 days with 5-days vs. 10-days of therapy in another RCT (n = 397). Clinical improvement was better for 5-days regimen vs. standard of care in one RCT (n = 600). Remdesivir did not decrease all-cause mortality (RR 0.71, 95%CI 0.39 to 1.28, I2 = 43%) and need for invasive ventilation (RR 0.57, 95%CI 0.23 to 1.42, I2 = 60%) vs. placebo at 14 days but had fewer SAEs; 5-day decreased need for invasive ventilation and SAEs vs. 10-day in one RCT (n = 397). No differences in all-cause mortality or SAEs were seen among 5-day, 10-day and standard of care. There were some concerns of bias to high risk of bias in RCTs. Heterogeneity between studies could be due to different severities of disease, days of therapy before outcome determination, and how ordinal data was analyzed., Conclusions: There is paucity of adequately powered and fully reported RCTs evaluating effects of remdesivir in hospitalized COVID-19 patients. Until stronger evidence emerges, we cannot conclude that remdesivir is efficacious for treating COVID-19., Competing Interests: The authors have read the journal’s policy and have the following potential competing interests: VP is a paid employee of MedErgy Health Group Inc., and PT is a paid employee of Hemex Health Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Objective: A systematic review and meta-analysis was performed to evaluate the safety and efficacy of drug-eluting stents (DES) vs bare-metal stents (BMS) in atrial fibrillation (AF) patients., Methods: We systematically searched 5 engines until May 2019 for cohort studies and randomized controlled trials (RCTs). Primary outcomes were major bleeding and major adverse cardiac events (MACE) including cardiac death, myocardial infarction, target vessel revascularization (TVR) or stent thrombosis. Effects of inverse variance random meta-analyses were described with relative risks (RR) and their 95% confidence intervals (CI). We also stratified analyses by type (triple [TAT] vs dual [DAT]) and duration (short-vs long-term) of antithrombotic therapy., Results: Ten studies (3 RCTs; 7 cohorts) including 10,353 patients (DES: 59.6%) were identified. DES did not show higher risk of major bleeding than BMS (5.6% vs 6.9%, RR 1.07; 95%CI, 0.89-1.28, p = 0.47; I 2  = 0%) or MACE (12% vs 13.6%; RR 0.96; 95%CI 0.81-1.13, p = 0.60; I 2  = 44%). Although, DES almost decreased TVR risk (6.4% vs 8.4%, RR 0.78; 95%CI, 0.61-1.01, p = 0.06; I 2  = 15%). Stratified analyses by type and duration of antithrombotic therapy showed no differences in major bleeding or MACE between both types of stents. In DES, long-term TAT showed higher major bleeding risk than long-term DAT (7.7% vs 4.7%, RR 1.48, 95%CI 1.08-2.03, p = 0.01; I 2  = 12%). For both types of stents, MACE risk was similar between TAT and DAT., Conclusions: In patients with AF undergoing PCI, DES had similar rate of major bleeding and MACE than BMS. DAT seems to be a safer antithrombotic therapy compared with TAT., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to develop a risk prediction model for major postoperative infection (MPI) after pediatric heart surgery and to validate the model of the Society of Thoracic Surgeons (STS)., Materials and Methods: We analyzed a retrospective cohort of 1,025 children who underwent heart surgery with cardiopulmonary bypass (CPB) from 2000 to 2010. We used a logistic regression model, which was validated., Results: Of the 1,025 patients, 59 (5.8%) had at least one episode of MPI (4.8% had sepsis, 1% had mediastinitis, 0% had endocarditis). Hospital mortality (63% vs. 13%; p < 0.001), as well as duration of postoperative ventilation (301.6 vs. 34.3 hours; p < 0.001) and intensive care unit stay (20.9 vs. 5.1 days; p < 0.001) were higher in patients with MPI. The predictive factors found were age, sex, weight, cyanotic heart disease, RACHS-1 3-4, Ross-modified functional class IV, previous hospital stay, and previous history of mechanical ventilation. The proposed model had a c-statistic of 0.80 (95% CI: 0.74-0.86) and was considered as clinically useful. The STS model showed a c-statistic of 0.78 (95% CI: 0.71-0.84) and a Hosmer-Lemeshow of 18.2 (P = 0.020). A comparison between the two models was made using an accurate Fisher test., Conclusion: A model with good performance and calibration was developed to preoperatively identify children at high risk for severe infection after cardiac surgery with CPB. The STS model was also validated and was found to have a moderate discrimination performance.

Background: Hydroxychloroquine and chloroquine have antiviral effects in vitro against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Purpose: To summarize evidence about the benefits and harms of hydroxychloroquine or chloroquine for the treatment or prophylaxis of coronavirus disease 2019 (COVID-19)., Data Sources: PubMed (via MEDLINE), EMBASE (via Ovid), Scopus, Web of Science, Cochrane Library, bioRxiv, Preprints, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry from 1 December 2019 until 8 May 2020., Study Selection: Studies in any language reporting efficacy or safety outcomes from hydroxychloroquine or chloroquine use in any setting in adults or children with suspected COVID-19 or at risk for SARS-CoV-2 infection., Data Extraction: Independent, dually performed data extraction and quality assessments., Data Synthesis: Four randomized controlled trials, 10 cohort studies, and 9 case series assessed treatment effects of the medications, but no studies evaluated prophylaxis. Evidence was conflicting and insufficient regarding the effect of hydroxychloroquine on such outcomes as all-cause mortality, progression to severe disease, clinical symptoms, and upper respiratory virologic clearance with antigen testing. Several studies found that patients receiving hydroxychloroquine developed a QTc interval of 500 ms or greater, but the proportion of patients with this finding varied among the studies. Two studies assessed the efficacy of chloroquine; 1 trial, which compared higher-dose (600 mg twice daily for 10 days) with lower-dose (450 mg twice daily on day 1 and once daily for 4 days) therapy, was stopped owing to concern that the higher dose therapy increased lethality and QTc interval prolongation. An observational study that compared adults with COVID-19 receiving chloroquine phosphate, 500 mg once or twice daily, with patients not receiving chloroquine found minor fever resolution and virologic clearance benefits with chloroquine., Limitation: There were few controlled studies, and control for confounding was inadequate in observational studies., Conclusion: Evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19 is very weak and conflicting., Primary Funding Source: Agency for Healthcare Research and Quality.

Purpose: Adaptive servoventilation (ASV) has been reported to show improvement in patients with sleep-disordered breathing (SDB) and heart failure (HF); however, its role as a second-line or adjunctive treatment is not clear. We conducted a systematic review and meta-analysis of new existing data including cardiac mechanistic factor, geometry, and cardiac biomarkers., Methods: We systematically searched for randomized controlled trials (RCTs) and cohort studies that assessed the efficacy or effectiveness of ASV compared to conventional treatments for SDB and HF in five research databases from their inception to November 2018. Random-effects meta-analyses using the inverse variance method and stratified by study design were performed., Results: We included 15 RCTs (n = 859) and 5 cohorts (n = 162) that met our inclusion criteria. ASV significantly improved left ventricular ejection fraction (LVEF) in cohorts (MD 6.96%, 95% CI 2.58, 11.34, p = 0.002), but not in RCTs. Also, the ASV group had significantly lower apnea-hypopnea index (AHI) in both cohorts (MD - 26.02, 95% CI - 36.94, - 15.10, p < 0.00001) and RCTs (MD - 21.83, 95% CI - 28.17, - 15.49, p < 0.00001). ASV did not significantly decrease the E/e' ratio in RCTs or in cohorts. Finally, ASV significantly decreased brain natriuretic peptide (BNP) in the cohorts (SMD - 121.99, CI 95% - 186.47, - 57.51, p = 0.0002) but not in RCTs. ASV did not have a significant effect on systolic blood pressure, diastolic blood pressure, and cardiac diameters., Conclusions: ASV therapy is associated with improvements of AHI in comparison to alternative treatments in patients with SDB and HF. ASV did not improve LVEF or E/e' ratios in randomized trials; other intermediate outcomes did not improve significantly.

Objective: To evaluate the association between preeclampsia (PE) and eclampsia (E) on subsequent metabolic and biochemical outcomes., Methods: Systematic review and meta-analysis of observational studies. We searched five engines until November 2018 for studies evaluating the effects of PE/E on metabolic and biochemical outcomes after delivery. PE was defined as presence of hypertension and proteinuria at >20 weeks of pregnancy; controls did not have PE/E. Primary outcomes were blood pressure (BP), body mass index (BMI), metabolic syndrome (MetS), blood lipids and glucose levels. Random effects models were used for meta-analyses, and effects reported as risk difference (RD) or mean difference (MD) and their 95% confidence interval (CI). Subgroup analyses by time of follow up, publication year, and confounder adjustment were performed., Results: We evaluated 41 cohorts including 3300 PE/E and 13,967 normotensive controls. Women were followed up from 3 months after delivery up to 32 years postpartum. In comparison to controls, PE/E significantly increased systolic BP (MD = 8.3 mmHg, 95%CI 6.8 to 9.7), diastolic BP (MD = 6.8 mmHg, 95%CI 5.6 to 8.0), BMI (MD = 2.0 kg/m 2 ; 95%CI 1.6 to 2.4), waist (MD = 4.3 cm, 95%CI 3.1 to 5.5), waist-to-hip ratio (MD = 0.02, 95%CI 0.01 to 0.03), weight (MD = 5.1 kg, 95%CI 2.2 to 7.9), total cholesterol (MD = 4.6 mg/dL, CI 1.5 to 7.7), LDL (MD = 4.6 mg/dL; 95%CI 0.2 to 8.9), triglycerides (MD = 7.7 mg/dL, 95%CI 3.6 to 11.7), glucose (MD = 2.6 mg/dL, 95%CI 1.2 to 4.0), insulin (MD = 19.1 pmol/L, 95%CI 11.9 to 26.2), HOMA-IR index (MD = 0.7, 95%CI 0.2 to 1.2), C reactive protein (MD = 0.05 mg/dL, 95%CI 0.01 to 0.09), and the risks of hypertension (RD = 0.24, 95%CI 0.15 to 0.33) and MetS (RD = 0.11, 95%CI 0.08 to 0.15). Also, PE/E reduced HDL levels (MD = -2.15 mg/dL, 95%CI -3.46 to -0.85). Heterogeneity of effects was high for most outcomes. Risk of bias was moderate across studies. Subgroup analyses showed similar effects as main analyses., Conclusion: Women who had PE/E have worse metabolic and biochemical profile than those without PE/E in an intermediate to long term follow up period., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To systematically evaluate the effects of bone anabolic therapies (BATs) - specifically, drug therapy with teriparatide, abaloparatide or romosozumab - on fractures, bone mineral density (BMD), and bone metabolites in postmenopausal osteoporosis., Methods: Six computerized engines were searched through to November 2018. We selected randomized controlled trials (RCTs) evaluating the effect of BATs on postmenopausal osteoporosis and with at least 6 months of follow-up. Controls were placebo, no treatment, or bisphosphonates. Primary outcomes were vertebral and non-vertebral fractures. Secondary outcomes were: BMD determined by dual energy X-ray absorptiometry at total hip, lumbar spine, and femoral neck; N-terminal propeptide of type I procollagen (PINP); C-terminal telopeptide of type I collagen (CTX); and severe adverse events (SAE). We followed the PRISMA guidelines for reporting, and used version 2 of the Cochrane risk-of-bias tool. Frequentist network meta-analyses were performed per outcome. Effects for dichotomous and continuous outcomes were expressed as relative risks and mean differences and their 95% confidence intervals. We used p-scores to rank best treatments per outcome., Results: Sixteen RCTs (n = 18,940) were evaluated. Mean ages ranged between 61 and 74 years, and follow-up times between 6 and 30 months. Four RCTs (n = 971) excluded patients with previous fractures. In contrast to placebo/no treatment, all BATs significantly reduced the risk of vertebral fractures, but no intervention significantly reduced the risk of non-vertebral fractures; abaloparatide ranked better than other interventions for both fracture types (p-scores: 0.95, and 0.89, respectively). All BATs significantly increased BMD at all locations in comparison with placebo/no treatment; romosozumab consistently ranked better than other interventions at all BMD locations (p-scores >0.86). Teriparatide ranked better than other interventions for increasing PINP. No differences in SAE were observed among treatments., Conclusions: Abaloparatide, romosozumab, and teriparatide are the best treatments, respectively, to reduce vertebral/non-vertebral fractures, increase BMD, and increase bone formation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Intermittent dieting may be an alternative to continuous dieting for weight reduction., Objective: To evaluate the effect of intermittent dieting versus continuous dieting on weight and body composition in overweight or obese adults., Design: A systematic review and meta-analysis of randomized controlled trials (RCTs). Five databases were searched until February 2018 for RCTs comparing intermittent versus continuous dieting. Intermittent dieting consisted of two types: regular intermittent was caloric restriction interspersed with days of weight maintenance or ad libitum eating; intensified intermittent was caloric restriction interspersed with days of even lower caloric restriction. Continuous was continual caloric restriction. Primary outcomes were weight, body fat, lean mass, waist circumference, hip circumference, and energy expenditure. Data were pooled by the inverse variance method using random-effects models and expressed as mean differences (MD) and their 95% confidence intervals (CI)., Results: Nine trials met the inclusion criteria (n = 782), six comparing regular intermittent vs continuous (n = 553), and three comparing intensified intermittent vs continuous (n = 229). Populations were heterogeneous: obese only in five studies, and overweight or obese (mixed) in four studies. Lean mass was significantly lower in regular intermittent vs continuous (MD -0.86 kg; 95% CI -1.62 to -0.10; p = 0.03). No differences were found for the remaining outcomes for both comparisons (regular intermittent or intensified intermittent vs continuous). There was low heterogeneity of effects across trials. Subgroup effects by time to follow-up, gender, per-protocol versus intention-to-treat, enforced exercise, and diabetes were similar to main analyses., Conclusions: This systematic review in obese and overweight individuals showed that regular intermittent dieting decreased lean mass compared to continuous dieting. There were no differences in effects for either intermittent vs continuous interventions across all other outcomes. In contrast to previous systematic reviews, this study suggested that lean mass is better preserved in continuous dieting compared to regular intermittent dieting.

Turmeric extract or active component curcumin may have anti-inflammatory effects in people with chronic inflammatory diseases. The effect of turmeric or curcumin on a wide range of inflammatory markers has not been evaluated in a systematic review. We performed a systematic review of randomized controlled trials (RCTs) evaluating the effects of oral turmeric or curcumin on inflammatory markers (CRP, hsCRP, IL-1, IL-6, TNF) in patients with a wide range of chronic inflammatory diseases. Pubmed, EMBASE, Scopus, the Web of Science, and the Cochrane library were evaluated until June 2018. Random effects meta-analyses with inverse variance methods and stratified by turmeric or curcumin were performed. Effects were expressed as mean differences (MD) and their 95% confidence intervals (CI). Risk of bias of RCTs was evaluated with the Cochrane tool. Nineteen RCTs were identified; included patients had rheumatic diseases, advanced chronic kidney disease with hemodialysis, metabolic syndrome, and cardiovascular diseases. Turmeric was the intervention in 5 RCTs (n = 356) and curcumin/curcuminoids in 14 RCTs (n = 988). Follow up times ranged between 4 and 16 weeks. One RCT had high risk of bias. In comparison to controls, turmeric or curcumin did not significantly decrease levels of CRP (MD -2.71 mg/L, 95%CI -5.73 to 0.31, p = 0.08, 5 studies), hsCRP (MD -1.44 mg/L, 95%CI -2.94 to 0.06, p = 0.06, 6 studies), IL-1 beta (MD -4.25 pg/mL, 95%CI -13.32 to 4.82, p = 0.36, 2 studies), IL-6 (MD -0.71 pg/mL, 95%CI -1.68 to 0.25, p = 0.15), and TNF alpha (MD -1.23 pg/mL, 95%CI -3.01 to 0.55, p = 0.18, 7 studies). There were no differences between turmeric and curcumin interventions. High heterogeneity of effects was observed for all markers across studies, except hsCRP. Other inflammatory markers such as IL-1 alpha, TNF beta, IL-17, and IL-22 had scarce data. Turmeric or curcumin did not decrease several inflammatory markers in patients with chronic inflammatory diseases., (Copyright © 2019 Elsevier Ltd. All rights reserved.)