Oregano (Origanum vulgare L.) Essential Oil Feed Supplement Protected Broilers Chickens against Clostridium perfringens Induced Necrotic Enteritis

Oregano (Origanum vulgare L.) is a well-known traditional medicine and a cooking spice. Recent practice has also applied the essential oil from oregano (OEO) in poultry due to its great potential for an antibiotic alternative. Our objective was to evaluate the potential effects of OEO (with carvacrol and thymol as the main active ingredient) on preventing necrotic enteritis (NE) caused by Clostridium perfringens (Cp) in chickens. In the feeding trial, a total of 450 one-day-old commercial Arbor Acres broilers were randomly assigned in 5 experimental groups during a 26-day production period (d19 to d 26 was the Cp challenge stage), and each group consisted of 6 replicate pens (15 birds each pen). All treatments were: basal diet (control group); basal diet and Cp challenge (model group); Cp challenge and 10 mg/kg enramycin (positive control group); Cp challenge and 200 mg/kg OEO product (OEO low dosage group, OEOL); Cp challenge and 300 mg/kg OEO product (OEO high dosage group, OEOH). OEO feed supplement at both dosages had significant effects on increasing the body weight gain (BWG) and reversing the dropped feed intake (FI) induced by Cp challenge. Histopathological changes in the ileums of broiler chickens with NE induced by Cp were alleviated by OEO, which was mutually confirmed by the intestinal lesion scores. Dosage did not influence the protective effect of OEO on intestinal lesion scores. Furthermore, OEO was found to have limited effects on tight junction-related gene expressions (Occludin and ZO-1). The broilers of the OEOL and OEOH groups significantly decreased the expression of TNF-α mRNA in the ileum and only the OEOH group was found to inhibit the IFN-γ expression of IFN- induced by Cp challenge. Finally, despite the fact that in vitro antibacterial effects by OEO were observed, considering its high minimum inhibitory concentration (MIC) value, we inferred that the protective effects by OEO against Cp challenge were not attributable to its direct antibacterial effects. We proposed OEO as a promising substitute for antibiotics against NE induced by Cp during poultry production.

Supplemental Bacillus subtilis PB6 Improves Growth Performance and Gut Health in Broilers Challenged with Clostridium perfringens

Clostridium perfringens (CP) is the principal pathogenic bacterium of chicken necrotic enteritis (NE), which causes substantial economic losses in poultry worldwide. Although probiotics are known to provide multiple benefits, little is known about the potential effects of Bacillus subtilis (B. subtilis) application in preventing CP-induced necrotic enteritis. In this study, 450 male Arbor Acres broilers were divided into 5 experimental treatments: A: basal diet (control group); B: basal diet and CP challenge (model group); C: CP challenge+10 mg/kg enramycin (positive control group); D: CP challenge+ 4 × 10 7 CFU / kg of feed B. subtilis PB6 (PB6 low-dosage group); and E: CP challenge+ 6 × 10 7 CFU / kg of feed B. subtilis PB6 (PB6 high-dosage group). There were 6 replicate pens per treatment with 15 broilers per pen. The present research examined the effect of Bacillus subtilis PB6 (B. subtilis PB6) on growth performance, mRNA expression of intestinal cytokines and tight junctions, and gut flora composition in broilers challenged with CP. The entire experiment was divided into two phases: the non-CP challenge phase (d0–18) and the CP challenge phase (d18–26). PB6 did not increase the growth performance during the first stage, but the PB6 high-dosage group was found to have larger body weight gain and ADFI during the CP challenge stage. Feed supplementation with PB6 reduced the lesion score of challenged chicks, with increased tight junction-related gene expression (occludin and ZO-1) and decreased TNF-α expression compared with CP-infected birds. A decrease in the abundance of Clostridium XI, Streptococcus, and Staphylococcus was observed after CP infection ( P < 0.05 ), while supplementation with PB6 restored the ileal microbial composition. In conclusion, administration of B. subtilis PB6 improved growth performance, enhanced intestinal barrier function, and mitigated intestinal inflammation/lesions, which might be due to its restoring effects on the ileal microbial composition in CP-challenged broilers.

Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study

Background Recent studies in rodents indicate that a combination of exercise training and supplementation with nicotinamide adenine dinucleotide (NAD+) precursors has synergistic effects. However, there are currently no human clinical trials analyzing this. Objective This study investigates the effects of a combination of exercise training and supplementation with nicotinamide mononucleotide (NMN), the immediate precursor of NAD+, on cardiovascular fitness in healthy amateur runners. Methods A six-week randomized, double-blind, placebo-controlled, four-arm clinical trial including 48 young and middle-aged recreationally trained runners of the Guangzhou Pearl River running team was conducted. The participants were randomized into four groups: the low dosage group (300 mg/day NMN), the medium dosage group (600 mg/day NMN), the high dosage group (1200 mg/day NMN), and the control group (placebo). Each group consisted of ten male participants and two female participants. Each training session was 40–60 min, and the runners trained 5–6 times each week. Cardiopulmonary exercise testing was performed at baseline and after the intervention, at 6 weeks, to assess the aerobic capacity of the runners. Results Analysis of covariance of the change from baseline over the 6 week treatment showed that the oxygen uptake (VO2), percentages of maximum oxygen uptake (VO2max), power at first ventilatory threshold, and power at second ventilatory threshold increased to a higher degree in the medium and high dosage groups compared with the control group. However, there was no difference in VO2max, O2-pulse, VO2 related to work rate, and peak power after the 6 week treatment from baseline in any of these groups. Conclusion NMN increases the aerobic capacity of humans during exercise training, and the improvement is likely the result of enhanced O2 utilization of the skeletal muscle. Trial registration number ChiCTR2000035138.

Effect of Dosage Reduction of Hypoglycemic Multidrug Regimens on the Incidences of Acute Glycemic Complications in People With Type 2 Diabetes Who Fast During Ramaḍān: A Randomized Controlled Trial

ObjectiveWe aimed to investigate the effect of dosage reduction of four hypoglycemic multidrug regimens on the incidences of acute glycemic complications in people with type 2 diabetes who fast during Ramaḍān.MethodsWe conducted an open-label, parallel-group, randomized controlled trial at a tertiary care center in Amman, Jordan. We recruited adults with type 2 diabetes who expressed an intention to fast during Ramaḍān and were adherent to one of four regimens—namely: metformin and glimepiride; metformin and vildagliptin; metformin and insulin glargine U100; or, metformin, insulin glargine U100, and human regular insulin. We randomly assigned participants in a 2:1 ratio to low- or regular-dosage therapy. The primary outcomes were the incidences of hypoglycemia and hyperglycemia during the 29 days of Ramaḍān 2017, and the secondary outcomes were the incidences of diabetic ketoacidosis and hyperosmolar hyperglycemic state during the same period.ResultsWe randomly assigned 687 participants to low-dosage therapy (n = 458) or regular-dosage therapy (n = 229) and included 678 (452 and 226, respectively) in the final analysis. The incidence of hypoglycemia was lower in the low-dosage group compared with the regular-dosage group (19 [4.2%] vs. 52 [23.0%], respectively; OR, 0.15 [95% CI, 0.08–0.26]; P &lt; 0.001). The incidence of hyperglycemia did not differ between the low- and regular-dosage groups (319 [70.6%] vs. 154 [68.1%], respectively; OR, 1.12 [95% CI, 0.79–1.58]; P = 0.5). No participants experienced diabetic ketoacidosis or hyperosmolar hyperglycemic state. Each 1% decrease in the baseline HbA1c concentration was associated with a 19.9-fold (95% CI, 9.6–41.5; P &lt; 0.001) increase in the odds of hypoglycemia, and each 1% increase in the baseline HbA1c concentration was associated with a 15.7-fold (95% CI, 10.0–24.6; P &lt; 0.001) increase in the odds of hyperglycemia.ConclusionDosage reduction decreases the incidence of hypoglycemia without a concomitant increase in the incidences of hyperglycemia, diabetic ketoacidosis, and hyperosmolar hyperglycemic state in people with type 2 diabetes who fast during Ramaḍān.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT04237493.

Exploring the Mechanism of Total Flavonoids of Drynariae Rhizoma to Improve Large Bone Defects by Network Pharmacology and Experimental Assessment

Drynariae Rhizoma (DR) has been demonstrated to be effective in promoting fracture healing in clinical use. In the study, we tried to predicate potential signaling pathways and active ingredients of DR via network pharmacology, uncover its regulation mechanism to improve large bone defects by in vivo and in vitro experiment. We total discovered 18 potential active ingredients such as flavonoids and 81 corresponding targets, in which mitogen-activated protein kinase (MAPK) signaling pathway has the highest correlation with bone defects in pathway and functional enrichment analysis. Therefore, we hypothesized that flavonoids in DR improve large bone defects by activating MAPK signaling pathway. Animal experiments were carried out and all rats randomly divided into TFDR low, medium, and high dosage group, model group and control group. 12 weeks after treatment, according to X-ray and Micro-CT, TFDR medium dosage group significantly promote new bone mineralization compared with other groups. The results of HE and Masson staining and in vitro ALP level of BMSC also demonstrated the formation of bone matrix and mineralization in the TFDR groups. Also, angiographic imaging suggested that flavonoids in DR promoting angiogenesis in the defect area. Consistently, TFDR significantly enhanced the expression of BMP-2, RUNX-2, VEGF, HIF-1 in large bone defect rats based on ELISA and Real-Time PCR. Overall, we not only discover the active ingredients of DR in this study, but also explained how flavonoids in DR regulating MAPK signaling pathway to improve large bone defects.

Ursodeoxycholic Acid at 18–22 mg/kg/d Showed a Promising Capacity for Treating Refractory Primary Biliary Cholangitis

Aim. To compare the response between the current recommended dosage 13–15 mg/kg/d and 20 mg/kg/d dose of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC) patients who do not respond completely to a standard dose of UDCA. Methods. We included 73 patients with poor response and randomized them into two groups to investigate whether increasing the dosage of UDCA was beneficial to nonresponders. Patients assigned to the 13–15 mg/kg/d group continued with standard therapy, and participants in the 18–22 mg/kg/d group switched to the higher dosage (18–22 mg/kg/d), with a follow-up of 12 months for both groups. The primary endpoints were the rate of response at 6 months and drug side effects. Results. According to the Paris 2 criteria, patients receiving 18–22 mg/kg/d UDCA achieved a response rate of 59.4% compared with 36.1% in the standard dosage group ( P = 0.046 ) at 6 months, respectively. At 12 months, the high-UDCA-dosage group achieved a response rate of 59.4% compared with 47.2% in the standard dosage group ( P = 0.295 ), respectively. Additionally, the risk score predicted by the UK-PBC model was lower in high-dosage UDCA-treated patients than in the standard dosage group (all P < 0.05 ). Side effects include diarrhea, nausea and vomiting, rash, and newly developed high blood pressure, which were mild and tolerated. Conclusions. Patients treated with the high UDCA dosage showed some advantages over those who continued the standard dosage in terms of biochemical remission and disease progression, indicating that standard therapy with UDCA for 6 months and then another 1 year with high UDCA dosage for nonresponders could be a treatment option before second-line therapy is recommended.

The Effect of Administering Extract of Java Plum Ethanol (Syzygium Cumini) to the Expression of the Molecular Adhesion 1 (Icam-1) on the Model of Huvecs Preeclampsia

Introduction: Preeclampsia is one of the causes of maternal mortality. In preeclampsia, endothelial dysfunction triggers the emergence of inflammatory cytokines and increases the expression of the molecular adhesion of ICAM-1. Inflammation of the preeclampsia can be controlled with the administration of anthocyanins. Java plum (Syzygium Cumini) contains anthocyanins that serve as antioxidants and anti-inflammatory. Purpose: This research aims to prove the influence of the administration of java plum (Syzygium Cumini) extracts on the expression of ICAM-1 on the model of HUVECs preeclampsia. Method: The research is conducted experimentally. It is done within the glass in a laboratory with two control groups namely negative control, three positive control, and six experimental groups (100ppm dose, 200ppm and 400ppm, incubation 1 hour, 3 hours, and 24 hours). HUVECs preeclampsia as a model of HUVECs preeclampsia within the glass. The ICAM-1 expression is used in the immunohistochemistry. The statistical analysis uses Two Way Anova test and regression test. Result: at the time of incubation of 1 hour, 3 hours, and 24 hours, there is no meaningful difference in the expression ICAM-1 (p = 0.392 > ∝). At the dose ICAM-1 of java plum, there is a meaningful difference between the positive control group with the dosage group of (p = 0.000 < ∝). Conclusion: An expression of ICAM-1 increases in preeclampsia conditions, administering java plum at a dose of 100 ppm, 200 ppm, and 400 ppm may decrease the expression of ICAM-1 in preeclampsia condition.

Risk of Polymyxin B-induced Acute Kidney Injury in Non-adjusted Dose Versus Adjusted Dose based on Renal Function: a retrospective cohort study

BackgroundThis study aimed to observe the difference in risk of polymyxin B-induced acute kidney injury with or without dose adjustment by patients’ renal function.MethodA retrospective cohort analysis was carried out for patients who were treated with polymyxin B in Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine from November 2018 to October 2019. Patients were divided into adjusted dosage group and non-adjusted dosage group depended on dosage adjustment with renal function or not. A comparison of acute kidney injury incidence between the two groups was the primary outcome of this research. The secondary outcome included hospital length of stay, microbiological cure, clinical cure, and 30-day mortality.ResultA total of 115 patients met the requirements of this study and were included in the analysis. Thirty-five patients were included in the non-adjusted dosage group and 80 in the adjusted dosage group. Patients from both groups had similar characteristics. The total daily dose of polymyxin B in the Non-adjusted dosage group was significantly higher than the adjusted dosage group (1.98 mg/kg/d vs 1.59 mg/kg/d, P=0.001). For the primary outcome of this research, no significant difference in the incidence of acute kidney injury was observed in these two groups (47.5% vs 37.14%, P=0.304), as well as the secondary outcomes, including hospital length of stay, microbiological cure, clinical cure, 30-day mortality.ConclusionDosing adjustment renally could not lower the risk of polymyxin B-induced acute kidney injury significantly. A non-adjusted dosing strategy of polymyxin B is recommended when patients suffered from various levels of renal impairment.

Hyperimmune anti-COVID-19 IVIG (C-IVIG) Therapy for Passive Immunization of Severe and Critically Ill COVID-19 Patients: A structured summary of a study protocol for a randomised controlled trial

Objectives The aim of this trial is to investigate the safety and clinical efficacy of passive immunization therapy through Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG: 5% liquid formulation), on severe and critically ill patients with COVID-19. Trial design This is a phase I/II single centre, randomised controlled, single-blinded, superiority trial, through parallel-group design with sequential assignment. Participants will be randomised either to receive both C-IVIG and standard care or only standard care (4:1). Participants The study is mono-centric with the participants including COVID19 infected individuals (positive SARS-CoV-2 PCR on nasopharyngeal and/or oropharyngeal swabs) admitted in institute affiliated with Dow University Hospital, Dow University of Health Sciences, Karachi, Pakistan. Consenting patients above 18 years that are classified by the treating physician as severely ill i.e. showing symptoms of COVID-19 pneumonia; dyspnea, respiratory rate ≥30/min, blood oxygen saturation ≤93%, PaO2/FiO2 <300, and lung infiltrates >50% on CXR; or critically ill i.e. respiratory failure, septic shock, and multiple organ dysfunction or failure. Patients with reported IgA deficiency, autoimmune disorder, thromboembolic disorder, and allergic reaction to immunoglobulin treatment were excluded from study. Similarly, pregnant females, patients requiring two or more inotropic agents to maintain blood pressure and patients with acute or chronic kidney injury/failure, were also excluded from the study. Intervention and comparator The study consists of four interventions and one comparator arm. All participants receive standard hospital care which includes airway support, anti-viral medication, antibiotics, fluid resuscitation, hemodynamic support, steroids, painkillers, and anti-pyretics. Randomised test patients will receive single dose of C-IVIG in following four dosage groups: Group 1: 0.15g/Kg with standard hospital care Group 2: 0.2g/Kg with standard hospital care Group 3: 0.25g/Kg with standard hospital care Group 4: 0.3g/Kg with standard hospital care Group 5 (comparator) will receive standard hospital care only Main outcomes The primary outcomes are assessment and follow-up of participants to observe 28-day mortality and, • the level and duration of assisted ventilation during hospital stay, • number of days to step down (shifting from ICU to isolation ward), • number of days to hospital discharge, • adverse events (Kidney failure, hypersensitivity with cutaneous or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, transfusion related acute lung injury (TRALI)) during hospital stay, • change in C-Reactive Protein (CRP) levels, • change in neutrophil lymphocyte ratio to monitor inflammation. Randomisation Consenting participants who fulfill the criteria are allocated to either intervention or comparator arm with a ratio of 4:1, using sequentially numbered opaque sealed envelope simple randomization method. The participant allocated for intervention will be sequentially assigned dosage group 1-4 in ascending order. Participants will not be recruited in the next dosage group before a set number of participants in one group (10) are achieved. Blinding (masking) Single blinded study, with participants blinded to allocation. Numbers to be randomised (sample size) Total 50 patients are randomised. The intervention arms consist of 40 participants divided in four groups of 10 participants while the comparator group consists of 10 patients. Trial Status Current version of the protocol is “Version 2” dated 29th September, 2020. Participants are being recruited. Recruitment started on June, 2020 and is estimated to primarily end on January, 2021. Trial registration This trial was registered at ClinicalTrials.gov, NCT04521309 on 20 August 2020 and is retrospectively registered. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1).

Role of Intravenous immunoglobulin in Non-Immunocompromised children With Severe Adenovirus Pneumonia: A Retrospective Observational Study

Background: Adenovirus pneumonia is a pulmonary infectious disease commonly occurring in children, and severe cases can lead to death and sequelae. Here, we aimed to observe the therapeutic timing and dosage of intravenous immunoglobulin(IVIg) in non-immunocompromised children with severe adenovirus pneumonia.Methods: This retrospective observational study investigated severe adenovirus pneumonia treated with IVIg in non-immunocompromised pediatric patients at a tertiary hospital in 2019. Participants were classified as early presenters (5-10 days of illness course) and later presenters (11-15 days) according to the timing of IVIg treatment. Patients’ clinical data were then analyzed in terms of different dosages of IVIg administration. Results: Among 202 patients enrolled, 128 were early presenters and 74 were later presenters during the study period. The later presenters had longer fever duration, more incidences of fungal coinfections, more demands for mechanical ventilation, and higher incidence of bronchiectasis than early presenters (P<0.05). For early presenters, no statistically significant differences in demands for advanced life support, outcomes and sequelae were observed between the two different dosage groups (P>0.05). For later presenters, shorter fever duration and lower usage of extracorporeal membrane oxygenation (ECMO) were observed in the high-dosage group than that in the low-dosage group (P<0.05). The incidence of post-infectious bronchiolitis obliterans (PIBO) and bronchiectasis was not significantly different between the two groups (P>0.05). The incidence of adverse events was 6.62% during IVIg infusion, showing no significant difference between the two groups (P>0.05).Conclusions: Early medical care and treatment with IVIg are very important to improve the prognosis of non-immunocompromised children with severe adenovirus pneumonia. For later presenters, children with severe conditions may benefit from a high IVIg dosage.