Altica viridicyanea feeding on normal‐ and antibiotic‐treated host plants using 16S rRNA amplicon sequencing; antibiotics have been shown to affect the body weight and development time in A. viridicyanea, suggesting that the gut bacteria of the normal sample were more diverse and abundant than those of the antibiotic‐fed group, and most of them were involved in various physical functions by enrichment analysis. Furthermore, we executed small RNA transcriptome sequencing using the two experimental groups to obtain numerous sRNAs, such as piRNAs, siRNAs, and known and novel miRNAs, by data mapping and quality control, and furthermore, a total of 224 miRNAs were identified as significantly differentially expressed miRNAs, of which some DEMs and their target genes participated in immune‐ and metabolism‐related pathways based on GO and KEGG annotation. Besides, regarding the regulatory roles of miRNA and target genes, a interaction network of DEM‐target gene pairs from eight immune‐ or metabolism‐related signaling pathways were constructed. Finally, we discovered that DEMs from above pathways were significantly positively or negatively correlated with gut bacterial alterations following antibiotic treatment. Collectively, the observations of this study expand our understanding of how the disturbance of gut bacteria affects miRNA profiles in A. viridicyanea and provide new valuable resources from extreme ranges for future studies on the adaptive evolution in insects.The gut bacteria involves in insect homeostasis by playing essential roles in host physiology, metabolism, innate immunity, and so forth. microRNAs (miRNAs) are endogenous small noncoding RNAs that posttranscriptionally regulate gene expression to affect immune or metabolic processes in insects. For several non‐model insects, the available knowledge on the relationship between changes in the gut bacteria and miRNA profiles is limited. In this study, we investigated the gut bacterial diversity, composition, and function from  Altica viridicyanea under antibiotic‐reared condition. The disturbance of gut bacterial microbiota affects miRNA profiles of A. viridicyanea feeding on antibiotic‐treated plants, which can lay the foundation for uncovering the adaptive evolution between gut bacteria–host interactions in Coleoptera.This finding provides the first genome‐wide identification and characterization of miRNAs and investigates the changes in gut bacterial microbiota in  With thApriona species with host niche competition, suggesting that they were annotated into degrading plant toxic secondary compounds based on KEGG enrichment , is a species of Altica Geoffroy (Coleoptera: Chrysomelidae) flea beetles and serves as a well‐known model of ecological speciation . In this study, we first used 16S rRNA amplicon sequencing by the Illumina HiSeq 2000 platform to detect the differences in the diversity and composition of gut bacterial communities in A. viridicyanea feeding on normal‐ or antibiotic‐treated host plants. Furthermore, sRNA‐seq analysis among above two experimental groups was performed on the A. viridicyanea guts to explore the characterization, expression patterns, and functional and regulatory roles of miRNAs. Lastly, a set of critical immune and metabolic differentially expressed miRNAs (DEMs) were selected, and the interaction relationships between DEMs and gut bacterial changes were executed based on bioinformatic prediction and Pearson correlation analysis. Taken together, this study can increase our understanding of the regulatory mechanisms of miRNAs and target genes in the insect gut and offer scientific data for future researches on the interaction between immunity or metabolism and gut bacteria in Coleoptera.22.1A. viridicyanea were collected from wild populations in Jizhou district , Tianjin, P.R. China on May 19, 2022. All beetles were reared in a growth chamber held at 25°C with 60% relative humidity (RH) and long‐day lighting conditions  and allowed to feed on its host plant G. nepalense, which was collected at the same location as insect samples. Next, newly born eggs and hatched larvae of A. viridicyanea were collected and kept in dishes with moist filter papers under above rearing conditions. The molted 2nd‐instar larvae were fed normal host leaves or host leaves completely submerged in antibiotic solution  for 5 min, until 10 days after adult emerging, which were sexually mature adults  were used to extract DNA with a Genomic DNA extraction Kit (QIAamp) following the manufacturer's instructions. Furthermore, the amount, purity, and integrity of each DNA sample were estimated by a NanoDrop 2100 (Thermo) and electrophoresis of a 1.0% agarose gel, respectively. The results showed a single bright band on the gel of each DNA sample of approximately 20,000 bp (base pairs), and the absorbance ratio of A260/A280 nm of all DNA samples ranging from 1.8 to 2.0 implied accessible DNA sample quality. Later on, the prepared DNA samples were diluted to 30 ng/μL with sterile water for 16S rRNA amplicon sequencing. In brief, all samples were amplified with the same cycle numbers to ensure the accuracy and dependability of library construction using the barcoded primers V338F (5′‐ACTCCTACGGGAGGCAGCAG‐3′) and V806R (5′‐CGACTACHVGGGTWTCTAAT‐3′). Moreover, a QuantiFluorTM‐ST blue fluorescence quantitative instrument was used to quantitatively detect the PCR (polymerase chain reaction) products. Next, the efficiency of the above PCR products was tested with 1.2% agarose gel electrophoresis, and then, they were purified with Agencourt AMPure XP beads (Beckman). The purified 16S rRNA amplicons were ligated with Illumina adapters (TruSeq DNA LT Sample Prep Kit), and the produced fragments with adapters were pooled in equimolar amounts. Finally, all the sequencing libraries from the above DNA products were built and sequenced with the Illumina HiSeq 2000 platform according to standard protocols at Beijing Genomics Institute (BGI) Technology Co., Ltd.A total of three biological replications from each treatment  to filter the raw data for quality check and splice the paired‐end sequences. Next, operational taxonomic units (OTUs) with sequence similarity were clustered through USEARCH (version 7.0.1090) software to discard chimeric sequences. RDP classifier (version 11.5) using the Bayesian algorithm conducted the taxonomic analysis based on the representative sequences of OTUs with a 97% similarity level using the I‐sanger cloud data analysis platform. In addition, alpha diversity was estimated by QIIME (version 1.9.1) workflow  were used to extract total RNA with TRIzol reagent (Invitrogen) according to the manufacturer's procedures. Moreover, the integrity, purity, and concentration of each RNA sample were estimated and assessed by 1.2% agarose gel electrophoresis and the OD260/OD280 ratio by an Agilent 2100 Bioanalyzer system (Agilent Technologies), respectively. In addition, remaining RNA after library construction was used to qRT‐PCR validation.A total of three biological replications from each treatment  software. Furthermore, the quality of clean reads was estimated by FastQC (version 0.10.1), and the information of Q20 and Q30, representing effective sequencing values, were statistically calculated. Then, we used Bowtie (version 1.1.2) to map clean data to the reference genome of 2.6ACGT101‐miR (version 4.2) (LC Sciences) was employed to filter out adapter dimers, junk, low complexity data, and common sRNA contaminants, including ribosomal RNA (rRNA), transfer RNA (tRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), and repeat sequences, from raw data. The remaining sRNAs were subsequently mapped to specific species precursors with miRbase (version 22.0), RNAcentral (version 16.0), and Rfam (version 13.0). In addition, we used miRbase (version 22.0) and miRDeep2 (version 0.1.3) in a BLAST  search to identify known or novel miRNAs . The significantly differentially expressed miRNAs were those with absolute log2 | fold change | >1 and p value <.001, calculated by edgeR package , and next, the correlation and principal component analysis (PCA) analyses were performed among all sRNA‐seq libraries based on RPKM (Reads Per Kilobase of exon model per Million mapped reads) using StringTie (version 1.3.0) software and DESeq R (version 1.10.1) package, respectively  and miRanda (version 3.3a) were applied to miRNA target prediction by identifying miRNA‐binding sites with computational target prediction algorithms for both combined and overlapping genes . In addition, raw reads have been submitted to the NCBI database under accession number PRJNA946034 and PRJNA946198.In order to explore the relationships between sRNA‐seq and 16S rRNA amplicon sequencing data, the Pearson correlation coefficients were calculated for the integrated analysis of the above sequencing results. Briefly, DEMs from eight signaling pathways and the top 10 changes in relative abundance of gut bacteria were selected to construct the heatmaps using R packages (version 2.15.3). Statistical significance was set at 2.102−ΔΔct method . cDNA samples were synthesized from remanent total RNA from the Section 33.1A. viridicyanea guts after quality control using 16S V3‐V4 rRNA amplicon sequencing. After alignment of these reads, a total of 488 OTUs were identified, and a Venn diagram of OTUs is shown in Figure Salmonella, Raoultella, Barnesiella, and Bacteroides, while Barnesiella and Bacteroides were the dominant taxa in the A group, and the abundances of Salmonella and Raoultella were decreased . Moreover, the gut bacterial communities obtained from the six sequencing groups were significantly clustered into two different groups in the PCoA plot , indicating that the gut bacteria of A. viridicyanea in the antibiotic‐fed group was represented by some biomarkers. Specifically, the taxa Bacteroideres, Bacteroidia, and Barnesiella were significantly enriched in the A group, and Delftia, Pedobacter, and Sphingobium were significantly enriched in the C group  and 94,961,924 (A group) raw reads, which were filtered to 98,807,924 and 92,356,655 clean reads, respectively, with average Q20 and Q30 scores of more than 98.97% and 96.87%  were 0.891–1.000 among the six sRNA‐seq groups based on FPKM values, representing the robustness of the biological replicates and reliability of the sRNA‐seq data  revealed strong aggregation of all sRNA‐seq samples (data not shown), and besides, the a Figure . Furtherd Figure . Finallyd Figure .3.5To explore the functional roles of miRNAs and target genes, we identified 2014 miRNAs targeting 11,395 genes, including 224 DEMs targeting 10,594 genes. The results demonstrated that target genes were involved in a wide range of biological functions, including biological process (BP), cellular component (CC), and molecular function (MF) by GO annotation. In detail, 47 GO terms were assigned to target genes; of these terms, 22 terms belonged to biological process, 14 terms belonged to cellular component, and 11 terms belonged to molecular function, including binding, followed by cell, cell part, cellular process, catalytic activity, and so forth Figure . As showTo clarify the functional pathways of DEMs and target genes, the KEGG enrichment results suggested that a total of 5152 target genes were annotated to 44 KEGG pathway subcategories from six categories, including cellular processes, environmental information processing, genetic information processing, human diseases, metabolism, and organismal systems Figure . The dom3.6A. viridicyanea.Based on the functional enrichments and target prediction, we randomly selected 23 DEMs and 133 target genes to construct a network map from four innate immune pathways, including Toll/Imd, JAK/STAT, MAPK‐fly, and NF‐κB signaling pathways, as well as four metabolism‐related pathways, including metabolism of xenobiotics by cytochrome P450, carbon metabolism, fatty acid metabolism, and glutathione metabolism. Concretely, nine upregulated DEMs and 14 downregulated DEMs were selected to build the interaction network Figure , and mea3.7Bacteroides, Barnesiella, Prevotella, Parasutterella, and Ruminococcus are not significantly positively correlated with DEMs in the Toll/Imd and NF‐κB signaling pathways, and they are less significantly associated with DEMs than those in the JAK/STAT and MAPK‐fly signaling pathways. Similarly, Bacteroides, Barnesiella, Prevotella, Parasutterella, and Ruminococcus were also not significantly positively associated with DEMs in four metabolism‐related pathways. Overall, the number of DEMs in eight pathways significantly negatively correlated with changes in the gut bacteria was larger than that with significantly positive correlation. Additionally, some DEMs, such as novel‐miRNA‐1066‐5p, novel‐miRNA‐879‐5p, novel‐miRNA‐981‐5p, novel‐miRNA‐872‐5p, and novel‐miRNA‐970‐5p, were conversely significantly association with different gut bacterial changes in same pathway.To determine the correlation relationships between two sequencing data, we selected the top 10 abundant changes in gut bacteria and 10 DEMs from each signaling pathway  to trigger mRNA degradation or translational suppression , with high economic value and ecosystem importance, was observed that its gut bacteria might influence host health by modulating immune responses  through antibiotic treatments, leading to upregulation of an antimicrobial peptide. Besides, many reports have validated that the Imd pathway mediates many aspects of the actions of gut bacteria such as Acetobacter pomorum and Lactobacillus plantarum, which play significant roles in promoting both immune and nonimmune functions through the Imd immune system in Drosophila ; formal analysis ; investigation ; methodology ; supervision ; visualization ; writing – original draft (lead); writing – review and editing . Yuan Wang: Investigation ; methodology ; resources ; writing – review and editing . Juhong Chen: Data curation ; investigation ; methodology ; resources ; software ; writing – review and editing . Siying Fu: Data curation ; formal analysis ; investigation ; writing – review and editing . Wenjun Bu: Project administration ; visualization ; writing – review and editing . Huaijun Xue: Funding acquisition ; investigation ; project administration ; supervision ; writing – review and editing .This work was financially supported by the National Natural Science Foundation of China (Grant Nos. 31672334 and 32170456) and the Fundamental Research Funds for the Central Universities (Grant No. 63213120).The authors declare no conflict of interest.None.Figure S1.Click here for additional data file.Figure S2.Click here for additional data file.Figure S3.Click here for additional data file.Figure S4.Click here for additional data file.Table S1.Click here for additional data file.Table S2.Click here for additional data file.Table S3.Click here for additional data file.Table S4.Click here for additional data file.Table S5.Click here for additional data file.Table S6.Click here for additional data file.Table S7.Click here for additional data file.Table S8.Click here for additional data file.Table S9.Click here for additional data file.


The prognosis of patients with relapsed or refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) is poor. Although patients who fail first‐line salvage chemotherapy are candidates for second‐line salvage chemotherapy, the optimal treatment strategy for these patients has not yet been established.The present, single‐center, retrospective study included transplant‐eligible patients with R/R DLBCL who received second‐line salvage chemotherapy with curative intent.Seventy‐six patients with R/R DLBCL received second‐line salvage chemotherapy. Eighteen (23.7%) patients were responders to the first‐line salvage chemotherapy. The overall response rate was 39.5%, and overall survival (OS) was significantly longer in patients who responded to second‐line salvage chemotherapy than those who did not. Forty‐one patients who proceeded to potentially curative treatment  had a better prognosis than those who did not. Among the 46 patients who failed to respond to the second‐line salvage regimen, only 18 (39.1%) could proceed to the curative treatments. However, among the 30 patients who responded to the second‐line salvage regimen, 23 (76.7%) received one of the potentially curative treatments. Among 34 patients who received CAR T‐cell therapy, OS was significantly longer in those who responded to salvage chemotherapy immediately prior to CAR T‐cell therapy than in those who did not respond. In contrast, the number of prior lines of chemotherapy was not identified as a statistically significant prognostic factor of survival. No significant difference was detected in OS between patients receiving ASCT and those receiving CAR T‐cell therapy after the response to second‐line salvage chemotherapy.In this study, we demonstrated that chemosensitivity remained a crucial factor in predicting survival outcomes following CAR T‐cell therapy irrespective of the administration timing, and that both ASCT and CAR T‐cell therapy were acceptable after the response to second‐line salvage chemotherapy. Patients with central nervous system (CNS) involvement were excluded.A pathology review based on the World Health Organization classification was performed by hematopathologists at our hospital.2.2The salvage regimens used in this study were based on etoposide, ifosfamide, cis‐ or carbo‐platin, bendamustine, cytarabine, or gemcitabine. The regimens listed in Table 2.3p < 0.05) were included in the multivariable analysis. Categorical variables were evaluated using Fisher's exact test. All statistical analyses were performed with R software (version 4.2.2) or EZR software (version 1.41).p < 0.05 was considered to indicate statistical significance.Time‐to‐event endpoints were evaluated using the Kaplan–Meier method, with differences between groups compared using the log‐rank test. Overall survival (OS) was defined as the period from the date of the first cycle of second‐line salvage chemotherapy to the date of last follow‐up or death from any cause. Progression‐free survival (PFS) was defined as the period from the date of the first cycle of second‐line salvage chemotherapy to the date of the last follow‐up, documented progression, relapse, or death from any cause. Multivariate analysis was performed for PFS and OS using the Cox proportional hazards model. Independent variables with at least marginal association with PFS/OS in univariable analysis  continued to respond to the second‐line salvage chemotherapy, and two (11.1%) had PD. Of the 58 patients with SD or PD after the first‐line salvage chemotherapy, 14 (24.1%) responded to the second‐line salvage chemotherapy, 17 29.3%) had SD, and 27 (46.6%) had PD. There was no clear relationship between the type of salvage regimen and response rate .The response rate to Pola‐BR  was 55.6% (5/9) and 33.3% (2/6) in the entire cohort and in patients who failed to respond to the first‐line salvage chemotherapy, respectively . Eleven patients responded and 28 patients did not respond to second‐line salvage chemotherapy. Among the 11 responders, five changed their chemotherapy regimen owing to renal failure, two were considered inadequate response for proceeding to CAR T‐cell therapy, and four changed their regimen for other reasons. In total, patients received a median of one cycle (range: 1–9) of the third‐line salvage chemotherapy Table . ResponsOf the 11 patients who responded to the second‐line salvage chemotherapy, six 54.5%) continued to respond to the third‐line salvage chemotherapy, one (9.1%) had SD, and four (36.4%) had PD. Of the 27 patients who had SD or PD after the second‐line salvage chemotherapy, three (11.1%) had CR or PR, three (11.1%) had SD, and 21 (77.8%) had PD. There was also no clear correlation between the type of chemotherapy and response .The response rate to Pola‐BR was 40.0% 6/15) and 27.3% (3/11) in the entire cohort and in patients who failed to respond to the second‐line salvage chemotherapy, respectively . Six‐month PFS for the entire cohort after the second‐line salvage chemotherapy was 35.8% , with a median PFS of 3.2 months   Table .4The present, real‐world study of patients with R/R DLBCL after second‐line salvage chemotherapy demonstrated that the ORR of the second‐line salvage chemotherapy was 39.5%. The patients who responded to the second‐line salvage chemotherapy and those who received ASCT, CAR T‐cell therapy, or allo‐HSCT had good survival outcomes. We demonstrated that chemosensitivity remained a critical factor in predicting survival outcomes following CAR T‐cell therapy, regardless of administration timing. Furthermore, both ASCT and CAR T‐cell therapy are viable therapeutic options after achieving a response to second‐line salvage chemotherapy.Consolidative high‐dose chemotherapy followed by ASCT has been part of the standard management of R/R DLBCL for the last 25 years.Randomized studies have produced no clear evidence of the superiority of one salvage regimen over another,The type of salvage regimen was not clearly associated with treatment response in this study. However, the response rate to Pola‐BR seemed to be higher than to other regimens even in patients who were previously resistant to salvage chemotherapy, although the differences were nonsignificant. A previous cohort study reported that Pola‐BR achieved the best ORR at 48.1% in patients who received a median of three prior treatment lines.In the present study, several clinical factors significantly affected PFS after the second‐line salvage chemotherapy, including the time to relapse, response to the first‐line salvage therapy, LDH, extranodal involvement, and IPI at the second‐line salvage therapy. These prognostic factors have been examined in previous studies in patients who received first‐line salvage chemotherapy.As illustrated in Figure Although high‐dose chemotherapy followed by ASCT has been the standard therapy for patients who respond to first‐line salvage chemotherapy, its role after second‐line salvage chemotherapy remains unclear. CAR T‐cell therapy is being increasingly used in patients who are refractory to first‐line salvage chemotherapy. However, as of yet there are few direct analyses comparing CAR T‐cell therapy with ASCT in the post‐second‐line salvage chemotherapy setting. Given that the efficacy of ASCT predominantly depends on chemosensitivity and that the response rate to chemotherapy generally decreases after each line of chemotherapy, not many patients benefit from ASCT after second‐line or subsequent salvage chemotherapy. However, a recent, retrospective, cohort study reported the encouraging finding of a 1‐year OS rate of 74% in patients who underwent ASCT after two or more lines of salvage chemotherapy.In our study, although more patients who received CAR T‐cell therapy were refractory to the second‐salvage chemotherapy than those who underwent ASCT, the prognosis of patients who received CAR T‐cell therapy was not significantly different from that of those who underwent ASCT. CAR T‐cell therapy may have the potential for superior clinical outcomes compared to ASCT. Actually, three randomized trials compared the efficacy of CAR T‐cell therapy with ASCT as second‐line therapy for DLBCL and reached different conclusions.The present study had some limitations. This was a retrospective study enrolling a small cohort with a relatively short follow‐up period. In particular, a treatment bias was induced by the physicians determining treatment decisions at their own discretion. However, it included a group of patients who received salvage immunochemotherapy in the same clinical setting. We anticipate that there will still be patients who will receive second‐line salvage chemotherapy for some reasons described above, even if CAR T‐cell therapy is viewed as the superior treatment option as second‐line therapy. We believe that this study can offer some useful insights into the management of R/R DLBCL patients.5In conclusion, our results suggested that the response to second‐line salvage chemotherapy was important to proceed to curative treatments and to improve clinical outcomes in patients with R/R DLBCL. The efficacy of CAR T‐cell therapy was found to be influenced by the responsiveness to salvage regimens, regardless of when CAR T‐cell therapy was administered. Moreover, our study suggested that the favorable OS was observed in patients who underwent ASCT or CAR T‐cell therapy following the response to the second‐line salvage chemotherapy, suggesting that ASCT and CAR T‐cell therapy were viable treatment options. However, the ORR was still insufficient, especially in patients who were refractory to prior salvage regimens. Improvement of the efficacy of salvage chemotherapy and refinement of treatment strategies for R/R DLBCL are urgent issues that await addressing.Yu Yagi: Conceptualization (lead); resources (lead); writing – original draft (lead). Yusuke Kanemasa: Resources (supporting); writing – review and editing (lead). Yuki Sasaki: Data curation (lead). Mina Sei: Resources (supporting). Takuma Matsuo: Resources (supporting). Kento Ishimine: Resources (supporting). Yudai Hayashi: Resources (supporting). Mano Mino: Resources (supporting). An Ohigashi: Resources (supporting). Yuka Morita: Resources (supporting). Taichi Tamura: Resources (supporting). Shohei Nakamura: Resources (supporting). Toshihiro Okuya: Resources (supporting). Takuya Shimizuguchi: Resources (supporting). Naoki Shingai: Resources (supporting). Takashi Toya: Resources (supporting). Hiroaki Shimizu: Resources (supporting). Yuho Najima: Resources (supporting). Takeshi Kobayashi: Resources (supporting). Kyoko Haraguchi: Resources (supporting). Noriko Doki: Resources (supporting). Yoshiki Okuyama: Resources (supporting). Tatsu Shimoyama: Conceptualization (lead); resources (lead); supervision (lead).Noriko Doki—Lecture Fees: Janssen, Novartis.The present, retrospective study was performed in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.Written informed consent was waived because the present study used clinical data retrospectively obtained from the hospital medical records.Figure S1.Click here for additional data file.Table S1.Click here for additional data file.Table S2.Click here for additional data file.Table S3.Click here for additional data file.Table S4.Click here for additional data file.


Zingiber zerumbet) has been used as one of the most popular herbal remedies to treat a wide range of common diseases. Ginger has been shown to have antioxidant and antibacterial activity. It has various bioactive chemicals that might be utilized as an alternative treatment option for many infectious diseases. The present study aimed to examine the biochemical profile of ginger, antioxidant, and antibacterial activity against selective endodontic microbes. Antioxidant was measured using DPPH and antibacterial activity was performed using disk diffusion tests. Streptococcus mutants, Enterococcus faecalis, Staphylococcus spp., and Lactobacillus spp. were tested for antibacterial activity. Before evaluating the dried extracts, all solvents were eliminated using rotary evaporation. The obtained IC50 value revealed that ethanol extract had the greatest antioxidant activity. Concerning each bacterium, the plant extracts demonstrated considerable antibacterial activity (p = .001). Ethanol extracts showed the strongest antibacterial activity against the studied microorganisms. This study highlights that the Zingiber zerumbet (Z. zerumbet) is a strong antibacterial herb against multidrug‐resistant (MDR) gram‐positive bacteria. It may also be employed as a possible natural antioxidant source.Antibiotic resistance is rising across the world. For a very long time, bitter ginger ( Zingiber zerumbet (Z. zerumbet) is a strong antibacterial herb against multidrug‐resistant (MDR) gram‐positive bacteria. It may also be employed as a possible natural antioxidant source.The present study aimed to examine the biochemical profile of ginger, antioxidant, and antibacterial activity against selective endodontic microbes. This study highlights that the  The ginger rhizomes were properly cleaned with distilled water after sample collection and then dried in the shade. The Department of Pharmacology, Saveetha Institute of Medical and Technical Science, Saveetha University (SU), where a voucher (HA#270917) of plant species was stored for subsequent reference, made the definitive identification of the plant using its vernacular name. The rhizomes of the ginger samples were carefully washed with sterilized distilled water to remove unwanted particles or dust that may lead to contamination of the final product. After that, it was air‐dried at room temperature (25°C). The plant was ground into a fine powder (500 g) after the drying process.For extraction of antibacterial contents of 2.2Zingiber zerumbet rhizome powder weighing 10 g was mixed thoroughly with 100 mL of distilled water (1:10) in a 250 mL glass container. A water bath was used to boil the mixture for 30 min at 35°C. The extract was boiled and then cooled to room temperature. The mixture or extract is then filtered by filter paper, kept at 5°C for further tests  was used to analyze the extracts for qualitative phytochemical screening. The following six standards were examined: sinapic acid, myricetin, gallic acid, kaempferol, chlorogenic acid, and caffeic acid. For analysis, the extracts were run through a 0.45 m syringe filter. The Agilent 1260 quaternary pump was installed in the HPLC analyzer . Then utilized a DAD detector. A linear gradient with different flow rates was used. The column was kept at a constant temperature of 25°C. At 280 nm, the chromatograms were captured. A software tool called CHEMSTATION was utilized for data analysis . This mixture was then isocratically eluted at a flow rate of 1 mL/min at 30°C to perform the chromatographic separation. A 360 nm wavelength was used for detection , 5 μL of 5 mM EDTA, 32.5 μL of 100 mM methionine, 10 μL of 2 mM riboflavin, and 121 μL of the plant sample was added in respective wells and kept at room temperature for 10 min. The absorbance was read at 560 nm on an ELISA plate reader  and SPSS software. The mean values and SD were used to define the data. T‐test was used to check the significance of using the antibacterial activity of extracts versus antibiotic susceptibility pattern of the tested isolates and DPPH scavenging activity at different concentrations. ANOVA was applied among and between the extracts and antibiotic susceptibility testing for the selected antibiotic. The 33.1Z. zerumbet that reduce and cap silver nanoparticles of zerumbet were qualitatively examined. Z. zerumbet's phytochemical evaluation is demonstrated in Table Z. zerumbet extracts revealed a high amount of secondary metabolites.The phytochemical components in an organic extract of 3.2Z. zerumbet extracts were separated in a total run time of 16 and 10 min, respectively, in the following order: gallic acid, chlorogenic acid, caffeic acid, sinapic acid, benzoic acid, myricetin, quercetin, and kaempferol (shown in Table The five phenolic and three flavonoid compounds in the 3.3Table Z. zerumbet) rhizome crude ethanol and aqueous extract of the rhizome are presented in Table Enterococcus faecalis.The results of the antibacterial activities of bitter ginger  followed by Streptococcus mutans (25.5 ± 0.5), Enterococcus faecalis (25.5 ± 0.5), and Lactobacillus spp. (10.5 ± 0.5 ZZEE).The antimicrobial activity of extracts was assessed and quantified by the presence or absence of inhibition zone, zone diameter in mm. The antimicrobial activity of ethanol and aqueous extracts of both were effective against gram‐positive bacterial strains except the aqueous extract of 3.43.4.1The antioxidant activity of two medicinal plant part extracts was done by two methods. Table 3.4.2The antioxidant activity of the ginger extract was assessed using the DPPH free radical scavenging test. The above table shows the antioxidant activity of both ginger extracts using DPPH. The positive control was ascorbic acid and the absorbance of all the extracts at different concentrations was compared with it. The highest scavenging activity was present in ZZAE (90.6%) at the highest concentration of 1 mg/mL which is nearest to that of ascorbic acid (95%) at the same concentration. The ZZEE showed less activity (43.9%), respectively, at the same concentration .Dental caries and periodontal infections are the most common dental disorders. Dental caries, which is mostly caused by 5Z. zerumbet extracts exhibit adequate antibacterial and antioxidant properties for each of their different solvent bases. Drug interaction, toxicity, dosage, and side effects of these extracts along with in vivo interaction and processing  must be studied as well to better understand their effects. This will make it easier to use these extracts as a treatment or preventive option for many diseases.According to the present study's findings, Ali A. Assiry: Conceptualization ; methodology ; visualization ; writing – original draft . Naveed Ahmed: Formal analysis ; methodology ; validation ; visualization ; writing – original draft . Abdulmajeed Almuaddi: Validation ; visualization ; writing – original draft . Ahmed Saif: Validation ; visualization ; writing – original draft . Mohammed Abdulrahman Alshahrani: Formal analysis ; validation ; writing – original draft . Roshan Noor Mohamed: Resources ; visualization ; writing – review and editing . Mohmed Isaqali Karobari: Conceptualization (lead); investigation ; methodology (lead); project administration (lead); supervision (lead); writing – review and editing (lead).This research received no external funding.The authors declare no conflict of interest.The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Saveetha University, Chennai, Tamil Nadu, India, with ethical clearance code: IHEC‐SDC‐FACULTY/21/ENDO/199.Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patient(s) to publish this paper.


The sulfur cathode of lithium‐sulfur (Li‐S) batteries suffers from inherent problems of insufficient mechanical strength and the dissolution of sulfur and polysulfides. Inspired by the extraordinarily resilient and strong binding force of the Great Wall binder, that is, the sticky rice mortar, we extracted highly branched amylopectin (HBA), the effective ingredient, as a low‐cost, nontoxic and environmentally benign aqueous binder for the sulfur cathode. The HBA‐based cells outperform the Li‐S batteries based on the traditional polyvinyldene diflouride (PVDF) binder and a lowly branched polysaccharide binder. The improved electrochemical performance in the HBA‐based cell could be attributed to two mechanisms. First, the branched structure of the HBA provides enhanced mechanical and adhesive properties, which allow for a robust electronic and ionic conductive framework to be maintained throughout the cathode after extended cycling. Second, the HBA shows enhanced polysulfide retention due to the polymer's abundant lone‐pair rich hydroxyl groups and the formation of C─S bonds between the HBA and polysulfides prohibits the shuttle effect of polysulfides. The improved mechanical properties and polysulfide retention function of the HBA binder facilitate the HBA‐based Li‐S battery to deliver a long cycle life of 500 cycles at 2 C while only displaying a capacity fading of 0.104% per cycle. Inspired by the extraordinarily resilient and strong binding force of the Great Wall binder, that is, the sticky rice mortar, we extracted highly branched amylopectin, the effective ingredient, as a low‐cost, nontoxic, and environmentally benign aqueous binder for high performance and long life sulfur cathode. Wind‐ and solar‐based renewable energy have made significant inroads into energy grids across the world, but their implementation is hindered by their variable power supply, reaching up to 20% variability for wind energy. Therefore, energy storage systems such as rechargeable batteries are being implemented to supplement renewable energy generators.As continual global population and economic growth increase society's demand for energy, the environmental consequences of energy production become more apparent.1 Sinc2 emissions produced by internal combustion engines. However, rechargeable batteries are limited by their cost, energy density, and toxic components. As a result, novel battery chemistries are being investigated so that these shortfalls can be avoided. Lithium‐sulfur (Li‐S) batteries are promising next‐generation batteries that possesses a greater energy density than state‐of‐the‐art lithium‐ion batteries (LIBs), without the use of toxic transition metals in the cathode. However, they are limited in their commercial application due to some intractable technical issues.Rechargeable batteries are also gaining traction in electric vehicles, which benefit from reducing CO engines.10 How This dissolution of the active materials at the cathode forms a concentration gradient, which causes the soluble species to migrate toward the anode, where they can be further reduced and damage the anode. These reactions cause a severe loss in Coulombic efficiency and rapid capacity fading. Additionally, the insulating nature of elemental sulfur (S8) as well as the solid discharge product in the Li‐S cell (Li2S2/Li2S) causes poor active material utilization and sluggish reaction kinetics, resulting in insufficient discharge capacity and poor performance at high C rates, respectively. The conversion from sulfur to Li2S is also accompanied by a ≈80% increase in volume, which causes damage to the electronic conducting network and electrode delamination from the current collector, again reducing the electrochemical performance in Li‐S cells. Finally, the use of the metallic lithium anode can cause dendrite formation, which may pierce the separator and causes operational safety concerns.The single greatest challenge hindering the practical application of the Li‐S battery is the polysulfide shuttle phenomenon (or effect), which arises from the fact that the lithium polysulfide reaction intermediates formed during cycling are readily soluble in the ether‐based electrolytes used in Li‐S cells.16 Thi anode, electrolyte, and separator of the Li‐S cell in order to improve the electrochemical performance. Of these, the cathode of the Li‐S cell has received particular attention through the development and successful application of multifunctional sulfur hosts. When appropriately designed, sulfur hosts in Li‐S batteries can simultaneously mitigate multiple challenges within the Li‐S cell. For example, sulfur hosts with immense void structures, such as hierarchical porous carbons, can provide the necessary volume to accommodate a sufficiently large sulfur loading in the cathode while also providing abundant channels for electrolyte penetration during cycling. Sulfur hosts with inherent electronic conductivity can improve active material utilization and facilitate rapid charging/discharging. Heteroatom, transition metal oxide, or transition metal sulfide‐doped sulfur hosts can provide soluble polysulfide anchoring points to reduce the shuttle effect and catalyze the electrochemical reaction, improving the discharge capacity, reducing the capacity fading, and improving the kinetics at high C rates. Well‐designed sulfur hosts can incorporate many of these features at once.Researchers in the field have directed their attention to the cathode,26 ano Thus, researchers have turned their attention to the binders in the Li‐S cathode so that the structural damage and electrode delamination can be addressed. By utilizing binders with superior adhesive properties, a robust cathode composite can be maintained throughout extended cycles. However, adhesion between electrode components is not the only role that a binder can play in a Li‐S cathode, as demonstrated through the use of multifunctional binders. These binders go beyond simply proving improved adhesive properties by filling some of the roles traditionally left to the sulfur host, including providing chemical polysulfide anchoring via their functional groups or improving the electronic conductivity of the composite cathode. Among these, bio‐derived binders, including those derived from cyclodextrin and gelatin have been widely applied in Li‐S cells due to their inherent mechanical properties, cost, chemical functionality, and environmental benignity.Although remarkably effective at alleviating the aforementioned challenges, sulfur hosts can do little in the way of maintaining the intimate contact between the components of the composite sulfur cathode.36 Thu  glycosidic bonds  and α(1→6) linkages (Scheme 8 g·mol−1). The different conformations of the two polysaccharides affect the resulting physical and chemical properties. Initially, starch is insoluble in water, but upon heating, amylose forms a nonviscous solution, whereas amylopectin remains insoluble and forms a viscous gel. The physical structure of the starch is also related to its digestibility, with starches ranging from rapidly digestible to resistant.Starch, mainly composed of the two polysaccharides, amylose Scheme  and amyl49  polysaccharide found in starch. With its highly branched structure, the starch extracted from sticky rice is expected to deliver an improved electrochemical performance in Li‐S cells compared to previous works that have not considered the degree of branching in the starch.Sticky (or glutinous) rice is a valuable starch source with favorable adhesive properties due to its high amylopectin content. Sticky rice has been used as a mortar ingredient in ancient China for over 3000 years56 and+ diffusion throughout the cathode. This improvement is particularly appealing as the HBA is derived from both an environmentally friendly source and extraction method, which could reduce the environmental impact of the Li‐S cell.This work applies HBA binder, which is near 100% amylopectin content, as a low‐cost and environmentally benign Li‐S cathode binder. For the control experiment, the lowly branched polysaccharide (LBP) binder is obtained from potatoes, which is composed of approximately 70% amylopectin and 30% amylose. As a result, the HBA binder displays improved mechanical properties and adhesion compared with the traditional Li‐S binder polyvinylidene difluoride (PVDF) and a mixed LBP binder. The HBA binder also displays the ability to chemically retard soluble lithium polysulfides due to its lone‐pair rich hydroxyl groups and C─S bond formation. These features allow the HBA‐based binder to deliver enhanced electrochemical performance in Li‐S cells compared to cells based on PVDF and LBP binders. The HBA‐based cell delivers a capacity fading as low as 0.104% over 500 cycles at a 2 C rate, superior rate kinetics, and better Li22.1Sticky (glutinous) rice was obtained from the local Asian supermarket Figure . The sti2.2The details of materials characterization and mechanical characterization can be found in Supporting Information.2.3−2. Electrodes with a sulfur loading of ≈2 mg·cm−2 were also fabricated for high sulfur load testing. Electrodes fabricated from 80% carbon black and 20% HBA were also fabricated for electrolyte stability testing. Half‐cells were fabricated in an argon‐filled glovebox using either an S/PVDF, S/LBP, or S/HBA cathode, a lithium foil counter electrode, polypropylene (Celgard 2300) separator, and 1 M LiTFSI in DOL/DME  with 0.2 M LiNO3 as the electrolyte. The electrolyte/sulfur (E/S) ratio was kept constant at 1 mg:20 μl for all half‐cells. The half‐cells underwent galvanostatic charge/discharge testing on a Neware Battery Testing System  with a 1.7–2.7 V voltage window in an oven set at 30 °C. For the 0.5 C (1 C = 1672 mA·g−1) and high‐loading 0.2 C testing, an electrochemical sulfur infiltration pre cycle of 0.05 C was performed before cycling at the specified rate. For the 2 C testing, a 0.2 C pre cycle was utilized. Electrochemical impedance spectroscopy (EIS) was carried out on a Biologic SP‐200  with the AC set to 5 mV and a frequency range of 10 mHz to 100 kHz. Cyclic voltammetry (CV) testing was also carried out on the Biologic SP‐200.For electrochemical testing, sulfur cathodes using PVDF, LBP, or HBA as a binder were fabricated with elemental sulfur, carbon black, and binder in a mass ratio of 60:30:10 and were denoted S/PVDF, S/LBP, and S/HBA, respectively. The electrode components were ground in a mortar and pestle before being made into an electrode slurry using NMP as the solvent. The slurry was cast using a gapped blade on carbon‐coated aluminum foil before being dried in a vacuum oven at 60 °C for 24 h and cut into disks with a diameter of 13 mm. The active material loading in the electrodes was approx. 0.5 mg·cm3 As a result, a simple separation is achieved by simply extracting the HBA in water, and a highly branched and environmentally benign binder is obtained. The obtained HBA and LBP binder were first characterized by TGA to qualitatively observe their thermostability  image from the S/HBA sample . The discharge capacity in the initial cycle for the S/PVDF, S/LBP, and S/HBA‐based cells are 751, 817, and 866 mAh·g−1, respectively. After 500 cycles, the S/PVDF, S/LBP, and S/HBA cells deliver a capacity of 285, 354, and 392 mAh·g−1, corresponding to a 0.124%, 0.113%, and 0.109% capacity fade per cycle, respectively. When the current density is increased to 2 C, the superior capacity retention of the S/HBA‐based cell is still highlighted in Figure  Despite this, the S/HBA cell presents the smallest capacity fade from the 4th cycle onward and delivers the highest discharge capacity of 328 mAh∙g−1 at the 500th cycle. The capacity fade per cycle during testing is 0.124%, 0.137%, and 0.104% for the S/PVDF, S/LBP, and S/HBA cells, with the fade per cycle for the S/HBA cell dropping to 0.0845% when calculated from the fourth cycle onward. The amount of active materials at the cathode is a crucial parameter for Li‐S battery commercialization. Therefore, S/PVDF, S/LBP, and S/HBA electrodes were fabricated with a high sulfur loading of roughly 2 mg∙cm−2 and subjected to charge/discharge testing at 0.2 C, with the results shown in Figure −1, a reversible capacity of 842 mAhg−1 at the 50th cycle, and a capacity fading of 0.278% per cycle over the tested range, again outperforming both the S/LBP and S/PVDF batteries. Thus, it can be concluded that S/HBA batteries have higher reversible capacity, long cycle stability, and sulfur loading than batteries made with PVDF or LBP binders.The electrochemical stability of HBA was tested based on electrodes consisting of 80% carbon black and 20% HBA which were assembled into half‐cells. These cells were then subjected to cyclic voltammetry at 0.05 mV·sn Figure 75 DesRate performance is another critical parameter for electrochemical cells because charging/discharging in real situations is rarely galvanostatic. Thus, to evaluate the performance under differing current densities, rate performance testing was carried out with the results for the S/HBA cell shown in Figure DLi) properties could be evaluated  against the square of the scan rate (v0.5) Re), charge transfer resistance (Rct), and interface/solid electrolyte interface resistance (Rint), respectively. As the S/HBA cell displays lower resistances in all cases (Table WO) impedance in the cells. By graphing the real portion of the impedance (Zʹ) in the linear region of the EIS spectra and ω−0.5  can be calculated through the equation shown in Equation 2S/Li2S2 formation remaining on the electrode surface. The S/LBP electrode displays a similar morphology to the S/HBA electrode, albeit with slightly more surface irregularities  analysis was carried out on the cycled electrodes, with the results shown in Figure 4−1 (0.101% fading per cycle) at 0.5 C and 328 (0.104% fading per cycle) at 2 C, which is remarkable in comparison to both the S/LBP and S/PVDF cathodes. Such an enhanced performance of the S/HBA cells can be explained through two mechanisms. First, the HBA possesses the ability to chemically retain soluble polysulfide molecules at the cathode as it possesses abundant lone‐pair rich hydroxyl groups along with the ability to form the C─S bonds with soluble polysulfides. Second, HBA displays outstanding mechanical properties that can help maintain a robust conductive network after extended cycling, facilitating the rapid electrochemical reaction kinetics of the charge and discharge processes and evidenced by the EIS and CV characterizations. Furthermore, HBA could be readily obtained from the environment, representing a low‐cost, nontoxic, and sustainable natural product. Therefore, this work inspires the modern battery industry to develop toward high performance, low‐cost, and environmentally friendly trends and sustainability.Natural polysaccharides binders, including HBA and LBP binders, were successfully extracted, characterized, and applied during the fabrication of sulfur cathodes  for Li‐S batteries. The S/HBA cathode significantly outperforms the conventional S/ PVDF and S/LBP cathodes due to the highly branched structure and abundant hydroxyl functional groups of the HBA. After 500 cycles, the S/HBA cathode could still deliver a reversible capacity of 396 mAh∙gExploration editorial board. The authors declare no conflict of interest.Shanqing Zhang is a member of the Luke Hencz and Hao Chen: conceptualization of the idea, experimentation, manuscript preparation. Zhenzhen Wu, Shangshu Qian, and Su Chen: critical experiment, data analysis, and mechanical properties testing. Xingxing Gu, Xianhu Liu, Cheng Yan, and Shanqing Zhang: conceptualization of the idea, manuscript preparation, and funding.Supporting informationClick here for additional data file.


Nausea and vomiting are symptoms associated with a lot of diseases and oral tablets may be unprofitable for patients especially those suffering from nausea and vomiting. Therefore, this study aimed to formulate a new meclizine and pyridoxine combination formula for chewable tablets and provide rapid drug absorption and decrease motion sickness. The new chewable formulation has been prepared to provide fast action, is more acceptable, and could be used for all age categories. Seven trials haves been carried out to prepare to find the suitable one where formula 7 of the chewable gum preparation exhibited good taste and hardness, while the gelatin formulation give an accepted formula after four trials with better taste and good acceptance. The prepared formulations give a dissolution profile of meclizine (95.53–102.8%) and pyridoxine (99.25 ± 115%) and assay (98 + 0.05–99.3 ± 0.8%) for meclizine and (97 ± 0.9–100.0 ± 0.08%) for the pyridoxine in three prepared formulations of chewable tablets. Followed by the evaluation, the formulation and testing them on human volunteers are carried out to confirm their effect to ensure acceptance and fast actions. The finding is promising for preparing a new route of administration of meclizine and pyridoxine combination to be used in the market. Formulation of oral dosage forms is suitable for various drugs, but they are challenging to formulate if the active substances have poor dissolution rates or low bioavailability. Therefore, different techniques have been used to overcome this problem and enhance the dissolution rate and solubility of the drug –4. One oChewable tablets are mostly chewed in the mouth before swallowing. The main aim of the chewable tablet is to give a proper unit dosage form of medication that can easily be given to children or to the elderly who have difficulty swallowing a tablet intact , 12. Chewas women (pregnancy and nonpregnancy) and the general community. Studying sample: random. Survey method: questionnaire. Studying Society: 153 cases.Sample size calculation for study: https://www.rasoft.com/samplesize.html Inclusion: pregnancy, children, and people traveling with motion sickness Exclusion: people have not suffered from motion sickness; women have not afforded it previously To estimate the preferable dosage form of meclizine and pyridoxin combination for nausea and vomiting treatment, an initial survey was conducted following the descriptive analysis of data, and the target population The materials used for preparation of chewable gum tablets were as follows: meclizine HCL , pyridoxine HCL , saccharine (sweetening agent), citric acid (flavoring agent), gum base, glycerol (humectant), and peppermint powder .The materials used for preparation of chewable tablets were as follows: meclizine HCL , pyridoxine HCL , saccharine (sweetening agent), citric acid (flavoring agent), gum base, xanthan gum , microcrystalline cellulose 101 (MCC) , glycerol (humectant), and peppermint powder .The materials used for preparation of gummy tablets were as follows: meclizine HCL , pyridoxine HCL , gelatin (base), saccharine (sweetening agent), citric acid (flavoring agent/souring), and methylparaben (preservative).A chewable tablet is prepared in three forms to be suitable and acceptable in different ages, which are gum-like, Mentos-like, and gummy-like as follows.The formulation was carried out by the direct compression method using various ratios of the directly compressible gum base. The excipients used were saccharine (sweeting agent), citric acid (flavor), and gum base glycerol (humectant). We grind saccharin and citric acid together until they become smooth, mix meclizine and pyridoxine with saccharine and citric acid, and add flavor and food dye which has been preground to be homogeneous, after mixing all ingredients together to form homogeneous gum base. Kneading lasts 15 minutes until it becomes homogeneous with all its components. After that, the prepared formula is then compressed into a tablet.The excipients used were saccharine (sweeting agent), citric acid (flavoring agent), gum base, xanthan gum (viscous agent), microcrystalline cellulose 101 (MCC) (binder), glycerol (humectant), and peppermint powder (flavoring agent). We grind saccharin and citric acid together until they becomes smooth, mix meclizine and pyridoxine with saccharine, citric acid, microcrystalline cellulose 101 (MCC), and xanthan gum (viscous agent), and add flavor and food dye which has been preground to be homogeneous, after mixing all ingredients together to form homogeneous gum base. Kneading lasts 15 minutes until it becomes homogeneous with all its components. Then, the prepared formula is then compressed into a tablet.The excipients used were gelatin (base), saccharin (sweeting agent), citric acid (flavoring agent/souring), and methylparaben (preservative).We take 1 g of gelatin and add citric acid, meclizine, pyridoxine, sorbitol, saccharin, and methylparaben with 10 ml water. Then, we mixed all together, then added color and flavor, and poured to a mold. The gelatin tablets are weighed separately for each one gram; after weighing gelatin tablets for each one gram separately, they are collected in plastic boxes in the presence of silica gel, which prevents moisture.Water was selected as media for the disintegration as the buccal pH is between 6.2 and 7.6. The results showed that the tablets are completely dissolved within 15 minutes, and this indicates that the tablets can dissolve completely without any stress by chewing there are other. A machine is applied for chewable tablets, but using this one was starting to give a clear picture about the possible disintegration of tablets.Tablets were randomly taken and weighed, and the mean weight was calculated. The percentage deviation of each chewing gum, from the mean, was calculated.Chewing gums and gummy tablets unlike tablets cannot be assayed by the conventional method through grinding the tablet and weighing an accurate amount of medicament and estimating its content. Therefore, the tablet has been dissolved and tested by TLC.  Petroleum ether : acetone : methanol  7 : 0.5 : 1The spot of meclizine and pyridoxine are applied on TLC and mobile phase used and compared to the results of spots displaced by new gelatin tablets that have been dissolved in water, and the same Rf was recorded for standard meclizine and pyridoxine to indicate the proper mixing of the active ingredients with other additives.The evaluation was carried out by the chew-out method. For evaluation of chewing gum consistency, the dummy chewing gums (without drug) were prepared according to the formula and then were given to the human volunteers to chew for a certain time.The assay of the different tablet preparation was performed using HPLC, and the HPLC system used was a Beckman Gold system, prepared with a detector set at 254 nm, and a UV-vis spectrophotometer was used to evaluate the maximum absorption wavelength for both medicines. Standard solutions of approximately 50 mg pyridoxine hydrochloride and 25 mg meclizine hydrochloride were precisely weighed and dissolved in a 100 mL mobile phase. Sample solutions tablets were ground and mixed well. The amount is equivalent to 50 mg pyridoxine hydrochloride, and 25 mg meclizine hydrochloride was weighed and moved to a 100 mL volumetric flask. A mobile phase was added, and the solution was shaken for 15 min. The volume was made up to 100 mL with a mobile phase, and the solution was centrifugated. The column packed with a C18 silica gel, a flow rate of 1.5 mL/min, and a mobile phase ) was used. The resulting solutions were shaken for 30 min, and the volume was made up with the mobile phase. The concentration was determined in triplicate, and the % of the assay was determined.The drug release has been determined by measuring the concentration of the drug released after 15, 30, and 45 minutes in the medium of 0.01 M HCl in dissolution apparatus 2 with 100 rpm by withdrawing 5 ml of this solution in each time interval and diluted in a 50 ml volumetric flask.(1) Standard (STD) Solution. 25 mg of meclizine HCl and 50 mg of pyridoxine HCL were taken into a 100 ml volumetric flask and dissolved in 10 ml methanol, then the solution was diluted with 0.01 M HCl. 5 ml of the solution was withdrawed and diluted in 50 ml volumetric flask. We put one tablet in each vessel and filter through a 0.45 μg micromembrane filter.(2) Assay of Pyridoxine HCL and Meclizine. Each tablet contains 25 mg meclizine HCl and 50 mg pyridoxine HCL anhydrous. λ = 230 nm. STD: prepared by dissolving in 100 ml HCl, then 10 ml was withdrawn to 50 ml flask and diluted with 0.1 M HCl. Sample (SP): crush the tablet and weigh an equivalent amount to 25 mg meclizine and 50 mg pyridoxine to 100 ml flask and dissolve in 10 ml methanol, then the volume is completed with 0.1 M HCl and withdrawn 10 ml to 50 ml volumetric flask and diluted with 0.1 M HCl.(3) Stationary Phase. Silica gel. Mobile phase: 550 ml of 0.01 M HCl +350 ml acetonitrile +100 ml methanol.(4) Dissolution of Meclizine and Pyridoxine HCL Medium. 900 ml of 0.07 M HCl, apparatus: 100 rpm. Time: 45 minutes. Std solution: 25 mg of meclizine HCl and 50 mg of pyridoxine HCL was weighed into 100 ml volumetric flask and diluted with 0.07 M HCl, then 5 ml of this solution was withdrawn and diluted in 50 ml volumetric flask. We put one tablet in each vessel and filter through a 0.45 μg micromembrane filter.Oral drug delivery is well known for many years because of the maximum broadly utilized routes of administration amongst all of the routes which have been employed for the systemic delivery of the drug via diverse pharmaceutical merchandise of different dosage paperwork. However, dysphagia  is common amongst all age corporations and greater, particularly with the pediatric, and geriatric populace not favorable, and might affect sufferers with nausea, vomiting, and motion illness headaches. Changing the form of meclizine and pyridoxine tablets into chewable tablets has been carried out in this research.153 questionnaires were submitted, and the results showed that 88% of the respondents suffered from vomiting-associated pregnancy, and 49% from motion sickness. 58% of the respondents are pregnant women. 40% of responses are preferring chewable tablets, 46% for oral intake, and 8.6% for effervescent tablets. Meclizine and pyridoxine combination is the most usable dosage form by the response.Three types of formulations were prepared. The first preparation is gummy-based preparation and is most suitable for kids, and the other formulation is the gum-like and Mentos-like preparation.Boswellia carterii which gives hard and bitter formulations. Then, beeswax and acacia were used instead, but the formula was very soft. Because no pharm gum could be used in most gum preparation, we replace it by using prepared gum in the market that contains coloring, sucrose, and gum base. The color and sucrose were removed by washing them several times with distilled water, then melted, and mixed with other excipients. The citric acids were added to mask the bitter taste of pyridoxine and in a combination of sucrose to give the sweet taste. Then, the estimation of chewing gum consistency is determined and summarized in Different base gum was used to prepare the gum-like formula using natural gums such as (1) Chewable Tablet: Mentos-Like Formulation. Four trials were carried out to get the most accepted formulation by volunteers and as consistency where the first three formulas were modified because of sour taste or the high elasticity that has been corrected by controlling the number of citric acid amounts, glycerin, and xanthan gum (than gum .(2) Gummy-Like Preparation. Seven formulations were prepared and failed because of different reasons such as contamination, sour preparation, and other problem. Different formulations were prepared because of the problem of contamination as gelatin is a good source of microbial contamination and is overcome by adding preservatives. Also, the softening of the formulation was changed till the right amount was carried out.Ten volunteers tested the consistency of the tablets, and most of them liked the preparation, except for two of them who had comments about the bitter and sour tastes; therefore, the formulation was approved and considered accepted, as displayed in (3) Preidentification by TLC of Chewing Guma/b  Rf = a) = 2.  Standard of meclizine (a) = 2.3 b = 7.2  Standard of pyridoxine (a) = 1.8  Sample of meclizine in gum tablet (a) = 2.3  Sample of pyridoxine in gum tablet (a/b  Rf =   Rf of meclizine (standard) = 2/7.2 = 0.27  Rf of pyridoxine (standard) = 2.3/7.2 = 0.3  Rf of meclizine in gum tablet (sample) = 1.8/7.2 = 0.25  Rf of pyridoxine in gum tablet (sample) = 2.3/7.2 = 0.3By comparing the result of pure meclizine and pyridoxine with the new gum formulation, it is shown that the formula gives the same spot at the same level of pyridoxine Rf (0.3) and meclizine Rf (0.25) compared to a standard drug that gives Rf (0.3) pyridoxine Rf (0.27) meclizine. This indicated that the formula was mixed and prepared correctly and was confirmed by giving the same Rf.(4) Preidentification by TLC of Gelatin Tableta/b  Rf = a) = 3.8  Standard of meclizine (a) = 3.2 (b) = 6.9  Standard of pyridoxine (a) = 3.9 and sample of pyridoxine in gelatin tablet (a) = 3.3  Sample of meclizine in gelatin tablet (a/b  Rf =   Rf of meclizine (standard) = 3.8/6.9 = 0.55  Rf of pyridoxine (standard) = 3.2/6.9 = 0.4  Rf of meclizine in gelatin tablet (sample) = 3.9/6.9 = 0.56t = 3.3/6.9 = 0.47  Rf of pyridoxine in gelatin table (sample) By comparing the result of pure meclizine and pyridoxine with our formulation, it is shown that our formula gives the same spot at the same level of pyridoxine Rf (0.47) and meclizine Rf (0.65) compared to standard drug that gives Rf (0.4) pyridoxine and Rf (0.55) meclizine. This indicates that the formula was mixed, prepared correctly, and mixed within all tablets, and all samples showed same RF and spot size.Tablet weight variation as displayed in The different tablet formulations were determined by HPLC and the assay of gum-like tablets, Mentos-like tablets, and gummy-like tablets gives the % of assay 98% ± 0.05, 99.3 ± 0.08, and 98.7 ± 0.4, respectively, for meclizine and 99.2 ± 0.02, 97 ± 0.09, and 100.9 ± 0.08 for pyridoxine. This is to ensure the formulations are well prepared .The result showed the dissolution profile for the three prepared formulations after different time intervals of 15, 30, and 45 min as summarized in Three types of chewable tablet formulations of meclizine and pyridoxine are prepared and give promising properties and are acceptable to the volunteers used.


Mesenchymal stem cells (MSC) have shown immense therapeutic promise in a range of inflammatory diseases, including acute respiratory distress syndrome (ARDS), and are rapidly advancing through clinical trials. Among their multimodal mechanisms of action, MSCs exert strong immunomodulatory effects via their secretome, which contains cytokines, small molecules, extracellular vesicles, and a range of other factors. Recent studies have shown that the MSC secretome can recapitulate many of the beneficial effects of the MSC itself. We aimed to determine the therapeutic capacity of the MSC secretome in a rat bacterial pneumonia model, especially when delivered directly to the lung by nebulization which is a technique more appropriate for the ventilated patient.E. coli pneumonia model, CM was instilled or administered by nebulization and lung injury and inflammation assessed at 48 h.Conditioned medium (CM) was generated from human bone marrow derived MSCs in the absence of antibiotics and serum supplements. Post-nebulization lung penetration was estimated through nebulization of CM to a cascade impactor and simulated lung and quantification of collected total protein and IL-8 cytokine. Control and nebulized CM was added to a variety of lung cell culture models and injury resolution assessed. In a rat MSC-CM was predicted to have good distal lung penetration and delivery when administered by nebulizer. Both control and nebulized CM reduced NF-κB activation and inflammatory cytokine production in lung cell culture, while promoting cell viability and would closure in oxidative stress and scratch wound models. In a rat bacterial pneumonia model, both instilled and nebulizer delivered CM improved lung function, increasing blood oxygenation and reducing carbon dioxide levels compared to unconditioned medium controls. A reduction in bacterial load was also observed in both treatment groups. Inflammatory cytokines were reduced significantly by both liquid and aerosol CM administration, with less IL-1β, IL-6, and CINC1 in these groups compared to controls.MSC-CM is a potential therapeutic for pneumonia ARDS, and administration is compatible with vibrating mesh nebulization. Acute respiratory distress syndrome (ARDS) is a severe disease of the lung with a continuing high mortality. It is diagnosed on the basis of acute onset not attributable to background disease, infiltration of blood or tissue derived cells to the airspace and impaired blood oxygenation levels, the last of which can be used to denote severity level . The mosin vitro and preclinical results now graduating to clinical trials  have recently risen to prominence in the field of inflammation therapeutics . Their ml trials . While bl trials , 11. To l trials . While min vitro work to apply MSC-CM to cell and animal models of pneumonia. We have also aimed to utilize the novel administration option of vibrating mesh nebulization to the airspace, which is a technique that requires a smaller dose and is likely to produce a stronger and faster effect as it is delivered directly to the affected organ. Of relevance, delivery of MSC themselves intratracheally has previously been shown to be effective in an ARDS model . After a further 7 days of incubation with medium refresh on the third day, MSC colonies were trypsinized, counted, and cryopreserved as passage 0. MSC markers were confirmed by flow cytometry as per the minimum criteria for MSC established by Dominici et al. (data not shown)  for nebulizer dynamics studies or vehicle for other studies. After 24 h, medium was aspirated, cells washed with PBS and flasks refed with 15 mL of MEMα with no additions, i.e., serum free medium (SFM). After 24 h of further incubation, conditioned medium (CM) was aspirated, centrifuged at 1,000 × g for 10 min to remove cells and cell debris. After that, CM was transferred into centrifugal concentrator units  with 3 KDa MWCO limit size membrane. Tubes were places in a centrifuge  with swinging rotor at 4,000 × g at 4°C until desired final volume. In addition, concentrated CM was transferred into dialysis tubes  with a pore size of 4 KDa MWCO. Dialyzer tubes were placed in closed buckets and exposed to PBS with a ratio of 500 mL of PBS per 100 μL of concentrated CM for 24 h at 4°C. The CM was then collected, aliquoted, and stored at −80°C.Human bone marrow derived MSCs were isolated from healthy donor tissue based on plastic adherence. Briefly, after obtaining informed consent, bone marrow aspirate was sampled from the iliac crest, diluted with minimum essential media alpha  containing 10% fetal bovine serum  and penicillin/streptomycin, and plated to tissue culture flasks  at 10t shown) . Cryoviag, 5 min) settled all the liquid to the bottom. This process took c. 1 min per mL of CM and recovery was c. 95% by volume.For all experiments where control and nebulized CM were to be compared, in a tissue culture cabinet a vibrating mesh nebulizer  was placed so that the lower part fitted into a 50 mL polypropylene tube and the contact points sealed with Parafilm. The controller box was turned on until the CM was passed through and condensed in the tube and a centrifugation  was defrosted, nebulized, and collected. The nebulizer was then washed with PBS and then inverted and washed again with PBS with aerosol collected each time. 10 mL of LPS-CM was then nebulized to a cascade impactor  under a normal breathing ventilation regimen (15 L per minute) and each collection plate and connector washed with 10 mL of PBS and collected. Finally, 10 mL of LPS-CM was applied to a simulated lung device , again under normal breathing ventilation, and the various collection filters washed with 10 mL PBS and collected. All samples were then analyzed for total protein content by BCA assay  and a representative cytokine quantified by ELISA as per manufacturer’s instructions .Reporter assays: A549-κB-luc cells were seeded to 96 well plates at 50,000 cells in 100 μL of medium per well and 50 μL of SFM, non-nebulized or nebulized and collected MSC-CM was added 24 h later. An inflammatory activation cocktail  was then added for a further 24 h, whereupon medium was aspirated, cells homogenized in luciferase substrate  and luminescence quantified in a Victor™ multilabel plate reader . Scratch wound assays: A549-κB-luc cells were seeded to 24 well plates at 200,000 cells in 1 mL of medium. When confluence was reached, a single scratch wound was performed on the cell monolayer using a 1,000 μL pipette tip, medium aspirated, and cells washed with PBS. 1 mL of fresh medium was then added to each well with 250 μL of SFM, non-nebulized or nebulized MSC-CM. At various timepoints up to 24 h, scratch wounds were imaged under light microscopy  and total remaining wound size quantified. Endotoxin inflammation model: BEAS2B were seeded to 96 well plates at 50,000 cells in 100 μL of medium per well and 50 μL of SFM, non-nebulized or nebulized and collected MSC-CM was added 24 h later. Escherichia coli derived lipopolysaccharide  was then added to each well at 1 μg/mL. After another 24 h, media was harvested for cytokine ELISA  and cell viability assessed through addition of fresh media with 3--2,5-diphenyltetrazolium bromide  at a final concentration of 0.5 mg/mL. After 2 h, media was aspirated, formazan crystals solubilized in 100 μL of DMSO, and absorbance read at 630 nm. Oxidative stress model: BEAS2B cells were seeded as above and MSC-CM added. Hydrogen peroxide (H2O2) was then added to a final concentration of 10 mM for 2 h and an MTT viability assays performed as described above.An A549 lung epithelial cell line incorporating an NF-κB driven luciferase reporter construct  was used for transcription factor assessment and scratch wound assays. A BEAS2B bronchial epithelial cell line  was used for other injury models. These were both cultured in RPMI-1640 (Sigma) with 10% FBS and penicillin/streptomycin. Direct bacterial inhibition: Overnight bacterial cultures were established from cryofrozen beads in 5 mL of Luria Broth  in an orbital shaker at 37°C, 220RPM, overnight. Bacterial strains used were a patient isolate Gram-negative E. coli  and a reference Gram-positive S. aureus . Serial dilution and plating to agar determined these cultures to be c. 5 × 109 and 10 × 109 CFU/mL, respectively. MSC-CM was either used directly or passed through a VMN and added to 96 well V-bottom plates at 200 μL per well. Bacteria was then added in 10 μL of PBS to give final concentrations of 1,000 or 10,000 CFU/μL. Plates were placed in an orbital shaker at 37°C, 220 RPM for 4 h and then centrifuged with a plate adaptor in a benchtop centrifuge at 2,000 × g for 10 min. Medium was aspirated, bacteria pellet resuspended in 200 μL and transferred to a flat bottomed 96 well plate. Absorbance was assessed at 650 nm in a multilabel plate reader (Victor™). A linear relationship between absorbance and CFUs has been previously established for these strains  for 72 h. Wells were aspirated and refed with 100 μL of pre-nebulized or control MSC-CM and LPS (100 ng/mL) added to simulate the pneumonia environment. 24 h later, zymosan particles were added (four particles per cell ratio) and phagocytosis allowed to proceed for 4 h. Wells were then imaged under fluorescent microscopy  with two fluorescent particles in a cell being considered positive for phagocytosis activity.All animal experiments were performed under the ethical approval of the Animal Care in Research Ethical Committee (ACREC) at the University of Galway and the regulatory approval of the Health Products Regulatory Agency (HPRA) Ireland.E. coli delivered intratracheally. Animals were maintained under anaesthesia for 1 h between bacteria administration and treatment and then given IT instillation or attached to a Flexivent small animal ventilator  for nebulization. Animals were ventilated with room air with 90 breaths per minute, flow rate 500 cc per minute and duty cycle 30%. 300 μL of MSC-CM was delivered to the animals via VMN IT over the course of approximately 5 min. In a separate group, animals were anesthetized and received 300 μL of MSC-CM by direct instillation IT. All animals were allowed to recover and returned to cages for observation.Adult male Sprague Dawley rats, 350–450 g, were used . Animals were anesthetized with inhalational isoflurane (2% in air) and a bolus of clinically isolated −1·h−1; Atricorium besylate, Aspe, Ireland) was administered to induce respiratory paralysis immediately prior to static lung compliance measurement. Animals were then given an anesthetic overdose and sacrificed by exsanguination.48 h later, animals were reanesthetized with medetomidine 1 mg/kg  and ketamine 75 mg/kg , and after confirmation of anesthesia intubated and attached to the ventilator. Ventilation regime was 90 breaths per minute, flow rate 500 cc per minute. Animals were tracheostomized and a canula inserted in the coronary artery for continuous blood pressure and heart rate monitoring. Arterial blood for gas and metabolite analysis was also taken from this canula intermittently . After 1 h, cisatracurium besilate , dried and stained with Haema-Gurr for 5 min followed by 5 min of ethanol destain and dried in air. Infiltrating cells were imaged under light microscopy (Leica) and total and neutrophil cell numbers counted. Cytokine multiplex: BAL was applied to a bead based cytokine multiplex assay  as per manufacturer’s instructions in a multiplex bead reader . Lung bacterial load: BAL was serially diluted and plated to Brilliance UTI Clarity agar plates (Fannin). 24 h later E.coli presence was confirmed by color of colonies and CFU counted.p < 0.05 considered significant.All data were analyzed using GraphPad Prism Software . Data were tested for normal distribution and significance determined by ANOVA, with Naïve MSC-CM applied to a cascade impactor by VMN showed delivery to compartments corresponding to airways of diameter 1.39–8.61 mm  showing E. coli LPS induced inflammation, MSC-CM significantly inhibited production of IL-1β  is not answered. It also remains to be determined in MSC-CM can address a more established pneumonia infection and for the therapeutic window to be calculated.There are some limitations to this study. Firstly, transformed cell lines can only be considered the first line of In summary, the direct nebulization of MSC-CM broadly recapitulated the antibacterial and anti-inflammatory capacity of the MSC itself widely described in the scientific literature. In addition, nebulization enhanced the immune cell and fluid clearance capacity of the MSC-CM, offering a promising delivery route for the MSC secretome in ARDS patients where instillation of liquid therapeutics should be avoided.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Animal Care in Research Ethics Committee (ACREC) at University of Galway.HEG: formal analysis, investigation, data curation, and writing—review and editing. SDM and CM: formal analysis, investigation, data curation, writing—review and editing, and supervision. JL: conceptualization, methodology, formal analysis, resources, writing—review and editing, and supervision. RM: conceptualization, methodology, formal analysis, investigation, resources, data curation, and writing—review and editing. DO’T: conceptualization, methodology, formal analysis, investigation, resources, data curation, writing—original draft, writing—review and editing, supervision, project administration, and funding acquisition. All authors contributed to the article and approved the submitted version.DO’T was supported by Health Research Board Ireland (ILP-POR-2017-024) and Science Foundation Ireland (13/RC/2073).RM is CSO of Aerogen Ltd.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Referral to nutrition care providers in the USA such as registered dietitian nutritionists (RDNs) for medical nutrition therapy (MNT) remains low. We summarize research on the effectiveness of MNT provided by dietitians versus usual care in the management of adults with dyslipidemia. Improvements in lipids/lipoproteins were examined. If reported, blood pressure (BP), fasting blood glucose (FBG) glycated hemoglobin (A1c), body mass index (BMI), and cost outcomes were also examined.The synthesis of three systematic reviews included thirty randomized controlled trials. Multiple MNT visits (3–6) provided by dietitians, compared with usual care, resulted in significant improvements in total cholesterol (mean range: − 4.64 to − 20.84 mg/dl), low-density lipoprotein cholesterol (mean range: − 1.55 to − 11.56 mg/dl), triglycerides (mean range: − 15.9 to − 32.55 mg/dl), SBP (mean range: − 4.7 to − 8.76 mm Hg), BMI (mean: − 0.4 kg/m2), and A1c (− 0.38%). Cost savings from MNT were attributed to a decrease in medication costs and improved quality of life years (QALY).Multiple MNT visits provided by dietitians compared with usual care improved lipids/lipoproteins, BP, A1c, weight status, and QALY with significant cost savings in adults with dyslipidemia and justify a universal nutrition policy for equitable access to MNT. Cardiovascular disease (CVD) is a leading cause of death in the USA and globally , 2. ReceDietitians provide MNT in various practice settings in the USA, such as hospitals, physician offices, private practice, and other healthcare facilities in conjunction with a multidisciplinary healthcare team. However, there is a universal lack of consistency in access to nutrition care in the USA . Apart fMNT is an evidence-based application of the Nutrition Care Process (NCP) by the dietitian •, 18–20 n = 193,385) to examine healthcare costs related to cardiovascular events (CVE) in individuals with hyperlipidemia, costs were highest in the acute (first 30 days) post CVE and remained high over 3 years of follow-up as compared to those without a CVE , blood pressure (BP), anthropometrics , and glycemic control (fasting blood glucose (FBG) and glycated hemoglobin (A1c)]. A systematic search was performed to identify systematic reviews meeting eligibility criteria and published over the past 5 years using multiple databases (Medline (Bbsco), CINHAL (EBsco), Cochrane CENTRAL (Ebsco), and Cochrane Database of Systematic Reviews (Ebsco). Search terms included condition/population , intervention , and study design  etc.). A total of three SRs ••, 34•• Three SRs were published in the last 5 years that evaluated the effectiveness of MNT in the management of adults with dyslipidemia ••, 34••.All three systematic reviews (30 RCTs) ••, 34•• Fifteen RCTs describe providing individual-level interventions , 63, 64,n = 838, seven RCTs)]  ••; (2) S19 RCTs) ••; and (10 RCTs) ••, 33•• Results from three systematic reviews consistently demonstrate the beneficial effects of MNT on dyslipidemia compared with usual care. Mohr et al. •• and SiThough the direction of findings was similar between the systematic reviews, those that had stricter inclusion criteria in relation to intervention rigor typically demonstrated greater effect sizes.An earlier narrative review by Jacobson et al. •• reportAlthough HDL-C is not considered a direct target of lifestyle therapy ••, low Hn = 872]  , 69 and n = 872] ••. The un = 872] ••.Improving lifestyle factors, which includes nutrition, has been shown to improve outcomes for heart disease risk , 68•, 70Beyond their nutrition expertise, another reason dietitians achieve significant lipid-lowering effects is that they arrange for help their patients need to make behavior changes. For dietitians, the 5A model  serves as a clinical framework for helping patients’ lifestyle behavioral changes while ensuring the individual’s autonomy •, 23, 26MNT should be seamlessly integrated into clinical practice and into the USA healthcare system for equity in nutrition care to mitigate ASCVD risk factors. CVD remains the leading cause of mortality in the USA and globally , 2. DyslMultiple MNT visits provided by dietitians are effective and cost beneficial in improving dyslipidemia and cardiometabolic risk factors such as overweight/obesity, elevated BP, and A1c compared to usual care. High-quality evidence from three recent SRs offers strong justification for increasing access to MNT care for dyslipidemia, overweight/obesity, hypertension, and hyperglycemia to mitigate the risks of ASCVD in conjunction with and/or without lipid-lowering medications. Treatment goals can be achieved when MNT provided by a DIETITIAN is combined with a pharmacological approach with significant cost savings. MNT is an evidence-based, cost-effective component of treatment to help combat the most prevalent and costly chronic conditions, including conditions contributing to poor COVID-19 outcomes. Improvement of efforts to increase awareness among healthcare providers in the USA on how to access dietitians and other nutritional services and resources is needed. Access to MNT is critical for seniors and communities of color that suffer from chronic disease health disparities, driven by reduced access to medical and nutrition care, healthy foods, and safe places to be active.In the USA, MNT by dietitians should be considered for reimbursement in the treatment of dyslipidemia, hyperglycemia, hypertension, and overweight/obesity as a standard of practice to optimize cardiovascular outcomes. The expansion of MNT legislation in the USA with advocacy from major influential medical societies is necessary to provide nutrition care to seniors and to close the gaps in health disparities. Further research is needed to include longer intervention periods.


Compared with usual care, multicomponent integrated care was associated with reduced risk for all‐cause mortality , cardiovascular mortality , all‐cause hospital readmission , heart failure‐related hospital readmission , and all‐cause emergency department visits . Heart failure‐related mortality  and cardiovascular‐related hospital readmission  were not significant. The top three quality improvement strategies for all‐cause mortality were promotion of self‐management , facilitated patient–provider communication , and e‐health . Multicomponent integrated care reduced risks for mortality , hospital readmission , and all‐cause emergency department visits among patients with chronic heart failure.To investigate the effectiveness of multicomponent integrated care on clinical outcomes among patients with chronic heart failure. We conducted a meta‐analysis of randomized clinical trials, published in English language from inception to 20 April 2022, with at least 3‐month implementation of multicomponent integrated care . The study outcomes were mortality  and healthcare utilization . We pooled the risk ratio (RR) using Mantel–Haenszel test. A total of 105 trials ( Chronic heart failure (CHF) is a progressive and disabling disease with a high burden of morbidity and mortality. To date, 64.3 million people are living with heart failure globally.Inability to leverage existing healthcare resources, inconsistency in practice implementation, and insufficient integration of patient values and preferences are the key contributing factors to the slow progress in improving clinical outcomes among patients with CHF.A quality teamwork benefits healthcare at different levels. These include organizational benefits , patients' benefits , and healthcare team's benefits (enhances patient‐provider communication and integration of care).Table The protocol was registered on PROSPERO (ID: CRD42020216275). We searched PubMed, EMBASE, Ovid, and the Cochrane Library for RCTs that were published from inception to 20 April 2022 using a combination of search terms Table S1.FigureTableWe defined multicomponent integrated care as the implementation of two or more quality improvement (QI) strategies from different domains, namely, the healthcare system, healthcare providers, and patients.Two reviewers (YFY and JXH) independently screened the titles and abstracts. Relevant studies were reviewed in full text. Using a standardized case record form, we extracted data including the year of publication, country, study design, healthcare settings, sample size, duration and type of intervention, study population characteristics, and clinical outcomes. We used the Cochrane risk of bias tool to assess the quality of included RCTs for selection bias, performance bias, detection bias, attrition bias, reporting bias, contamination bias, and other biases.For binary outcomes, we used the Mantel–Haenszel method to calculate the risk ratio (RR) and 95% confidence interval (CI). For continuous outcomes, we calculated the standardized mean difference (SMD) with 95% CI using the inverse variance method. Trial data reported as median and interquartile range (IQR) were uniformly converted to mean ± standard deviation (SD) for continuous outcomes.Patients with CHF who received usual care as per the trial's routine practice were defined as the control group. There were seven trials that used an active comparator design.I2 statistics to assess study heterogeneity. An I2 of <40%, 40–60%, and >60% indicates no, moderate, and substantial heterogeneity, respectively.P‐value of the chi‐square test was <0.1 or the I2 value was >50%, we used random‐effects models; otherwise, we selected fixed‐effects models to pool the RR. We also conducted a sensitivity analysis using random‐effects models for all outcomes. We assessed publication bias using the funnel plots and Egger's regression test.P‐value < 0.05 was considered statistically significant.We used n = 37 607 patients with CHF) were eligible , continuous QI , facilitated patient–provider communication , and patient education .Of the 6164 RCTs screened, 105 RCTse Figure 1. TableFigure FigureTableGiven the nature of the intervention wherein blinding of the study personnel and participants was not possible, 77% of the included RCTs had a high risk for performance bias Figure S1. TherI2 = 17%; n = 93 RCTs)    for any causes , 0.84  for heart failure‐related cause  for cardiovascular‐related cause   and emergency department visit . There was no statistically significant difference in the number of all‐cause readmission  and cardiovascular‐related readmission . The sensitivity analysis using random‐effects models also showed consistent results , facilitated patient–provider communication , and e‐health  , team change , facilitated patient–provider communication , e‐health  and continuous QI  were the most effective QI strategies  and clinician education  were the most effective QI strategies  except for electronic patient registry, audit and feedback, clinician education, and patient reminder system  showed significant association  and continuous QI  were associated with a reduced risk for emergency department visit . On the other hand, compared with the usual care group, the intervention group reported an increased use of β‐blockers , aldosterone antagonist , and diuretics .We reported the subgroup analysis (baseline vs. post‐intervention) on the changes of use of renin–angiotensin system (RAS) blockers, β‐blockers, aldosterone antagonist, and diuretics FigureS9. TheIn the present meta‐analysis of 105 RCTs, implementation of multicomponent integrated care for 3 months or more was associated with a 10–30% reduced risk for mortality , hospital readmission , and all‐cause emergency department visits among patients with CHF. These benefits were observed in addition to usual care. Previously published meta‐analysis (i) included fewer studies and/or a mixture of RCTs and observational cohort studies, (ii) reported fewer subtypes of clinical outcomes , and (iii) focused on single health domain while the present meta‐analysis used a stricter definition of multicomponent integrated care.Among different QI strategies, patient self‐management, facilitated patient–provider communication, team change, clinician reminder, and e‐health were the most effective QI strategies to reduce risk for mortality among patients with CHF. These findings were broadly aligned with a meta‐analysis of multicomponent integrated care on cardiometabolic risk factors among patients with Type 2 diabetes.Clinician reminder system can be an effective tool to provide support and assistance to the healthcare providers for improving care delivery. Its effectiveness among patients with CHF depends on the clinical context.In the present meta‐analysis, the commonly implemented e‐health tools were telemonitoring  and e‐learning . Other studies involving patients with chronic kidney disease revealed the benefits of e‐health in promoting patient empowerment and self‐care efficacy.RAS blockers/angiotensin receptor neprilysin inhibitors, β‐blockers, aldosterone antagonists, and sodium‐glucose co‐transporter‐2 inhibitors are the four pillars of CHF management, which can prevent mortality and reduce healthcare utilization.We acknowledged several study limitations. First, there were RCTs in which details of the intervention and usual care groups were not clearly described. This created challenges to assess the complexity and intensity of study interventions. Second, due to limited data, we were unable to conduct subgroup analyses by the type of heart failure, namely, heart failure with preserved ejection fraction (HFpEF), mildly reduced ejection fraction (HFmrEF), and reduced ejection fraction (HFrEF), as well as by the status of co‐existing chronic kidney disease. Third, a low number of RCTs in the present meta‐analysis that captured heart failure‐related mortality as a key clinical outcome could potentially explain its insignificant results. Of note, heart failure becomes the centre‐stage in chronic disease management after the positive results of the EMPA‐REG Outcome trial in 2015.Multicomponent integrated care can reduce mortality , hospital readmission , and all‐cause emergency department visits among patients with CHF. Future research on patient‐reported outcomes and cost‐effectiveness of multicomponent integrated care is needed before its large‐scale implementation especially in LMICs.No potential conflict of interest relevant to this article was reported.This work was supported by the UK–Malaysia Joint Partnership on Non‐Communicable Diseases under the Malaysia Partnership and Alliances in Research (MyPAiR), funded by the Ministry of Education, Malaysia, and Medical Research Council, United Kingdom (Grant Number: IF076‐2019). The funders did not have any role in the design, interpretation of the study, or the decision to publish the results.Figure S1. Risk of bias assessment.Figure S2. Funnel plots of publication bias in the meta‐analysis.Figure S3. Forest plots of heart failure‐ and cardiovascular‐related mortality and hospital readmissions in patients with chronic heart failure.Figure S4. Meta‐analysis results of all‐cause mortality in patients with chronic heart failure using the random‐effects models.Figure S5. Forest plots of heart failure‐ and cardiovascular‐related mortality and hospital readmissions in patients with chronic heart failure using the random‐effects models.Figure S6. Forest plots of the number of events  using the fixed‐effects models.Figure S7. Forest plots of the number of events  using the random‐effects models.Figure S8. Effects of individual quality improvement strategies on healthcare utilization in patients with chronic heart failure.Figure S9. Use of medication therapy from baseline to the end of intervention in patients with chronic heart failure.Table S1. Search strategy for meta‐analysis and systematic review.Table S2. Definitions of quality improvement strategies in chronic heart failure from previous meta‐analysis (1).Table S3. Key characteristics of the 105 included randomised clinical trials.Table S4. Assessment of publication bias using the Egger's test.Table S5. Meta‐analysis results of mortality and hospital readmission, stratified by individual quality improvement strategy.Click here for additional data file.