scholarly journals Short- and long-term effects of amoxicillin/clavulanic acid or doxycycline on the gastrointestinal microbiome of growing cats

2021 ◽  
Author(s):  
Evangelia Stavroulaki ◽  
Jan S. Suchodolski ◽  
Rachel Pilla ◽  
Geoffrey T. Fosgate ◽  
Chi-Hsuan Sung ◽  
...  
Keyword(s):  
Clavulanic Acid ◽  
Antibiotic Treatment ◽  
Control Group ◽  
Rrna Gene ◽  
Upper Respiratory Tract ◽  
Long Term Effects ◽  
Microbial Composition ◽  
Increased Risk ◽  
Group 15 ◽  
Amoxicillin Clavulanic Acid

Antibiotic treatment in early life influences gastrointestinal (GI) microbial composition and function. In humans, the resultant intestinal dysbiosis is associated with an increased risk for certain diseases later in life. The objective of this study was to determine the temporal effects of antibiotic treatment on the GI microbiome of young cats. Fecal samples were collected from cats randomly allocated to receive either amoxicillin/clavulanic acid (20 mg/kg q12h) for 20 days (AMC group; 15 cats) or doxycycline (10 mg/kg q24h) for 28 days (DOX group;15 cats) as part of the standard treatment of upper respiratory tract infection. In addition, feces were collected from healthy control cats (CON group;15 cats). All cats were approximately two months of age at enrolment. Samples were collected on days 0 (baseline), 20 or 28 (AMC and DOX, respectively; last day of treatment), 60, 120, and 300. DNA was extracted and sequencing of the 16S rRNA gene and qPCR assays were performed. Fecal microbial composition was different on the last day of treatment for AMC cats, and 1 month after the end of antibiotic treatment for DOX cats, compared to CON cats. Species richness was significantly greater in DOX cats compared to CON cats on the last day of treatment. Abundance of Enterobacteriales was increased, and that of Erysipelotrichi was decreased in cats of the AMC group on the last day of treatment compared to CON cats. The abundance of the phylum Proteobacteria was increased in cats of the DOX group on days 60 and 120 compared to cats of the CON group. Only minor differences in abundances between the treatment groups and the control group were present on day 300. Both antibiotics appear to delay the developmental progression of the microbiome, and this effect is more profound during treatment with amoxicillin/clavulanic acid and one month after treatment with doxycycline. Future studies are required to determine if these changes influence microbiome function and whether they have possible effects on disease susceptibility in cats.

scholarly journals Short- and long-term effects of amoxicillin/clavulanic acid or doxycycline on the gastrointestinal microbiome of growing cats

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0253031
Author(s):  
Evangelia M. Stavroulaki ◽  
Jan S. Suchodolski ◽  
Rachel Pilla ◽  
Geoffrey T. Fosgate ◽  
Chi-Hsuan Sung ◽  
...  
Keyword(s):  
Clavulanic Acid ◽  
Antibiotic Treatment ◽  
Control Group ◽  
Rrna Gene ◽  
Upper Respiratory Tract ◽  
Long Term Effects ◽  
Microbial Composition ◽  
Increased Risk ◽  
Group 15 ◽  
Amoxicillin Clavulanic Acid

Antibiotic treatment in early life influences gastrointestinal (GI) microbial composition and function. In humans, the resultant intestinal dysbiosis is associated with an increased risk for certain diseases later in life. The objective of this study was to determine the temporal effects of antibiotic treatment on the GI microbiome of young cats. Fecal samples were collected from cats randomly allocated to receive either amoxicillin/clavulanic acid (20 mg/kg q12h) for 20 days (AMC group; 15 cats) or doxycycline (10 mg/kg q24h) for 28 days (DOX group;15 cats) as part of the standard treatment of upper respiratory tract infection. In addition, feces were collected from healthy control cats (CON group;15 cats). All cats were approximately two months of age at enrolment. Samples were collected on days 0 (baseline), 20 or 28 (AMC and DOX, respectively; last day of treatment), 60, 120, and 300. DNA was extracted and sequencing of the 16S rRNA gene and qPCR assays were performed. Fecal microbial composition was different on the last day of treatment for AMC cats, and 1 month after the end of antibiotic treatment for DOX cats, compared to CON cats. Species richness was significantly greater in DOX cats compared to CON cats on the last day of treatment. Abundance of Enterobacteriales was increased, and that of Erysipelotrichi was decreased in cats of the AMC group on the last day of treatment compared to CON cats. The abundance of the phylum Proteobacteria was increased in cats of the DOX group on days 60 and 120 compared to cats of the CON group. Only minor differences in abundances between the treatment groups and the control group were present on day 300. Both antibiotics appear to delay the developmental progression of the microbiome, and this effect is more profound during treatment with amoxicillin/clavulanic acid and one month after treatment with doxycycline. Future studies are required to determine if these changes influence microbiome function and whether they have possible effects on disease susceptibility in cats.

scholarly journals Ultrafine particles altered gut microbial population and metabolic profiles in a sex-specific manner in an obese mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kundi Yang ◽  
Mengyang Xu ◽  
Jingyi Cao ◽  
Qi Zhu ◽  
Monica Rahman ◽  
...  
Keyword(s):  
Ultrafine Particles ◽  
Microbial Population ◽  
Phosphate Buffer Solution ◽  
Biodiesel Fuel ◽  
Control Group ◽  
Obese Mouse ◽  
Rrna Gene ◽  
Obese Mice ◽  
Microbial Composition ◽  
Increased Risk

AbstractEmerging evidence has highlighted the connection between exposure to air pollution and the increased risk of obesity, metabolic syndrome, and comorbidities. Given the recent interest in studying the effects of ultrafine particle (UFP) on the health of obese individuals, this study examined the effects of gastrointestinal UFP exposure on gut microbial composition and metabolic function using an in vivo murine model of obesity in both sexes. UFPs generated from light-duty diesel engine combustion of petrodiesel (B0) and a petrodiesel/biodiesel fuel blend (80:20 v/v, B20) were administered orally. Multi-omics approaches, including liquid chromatography–mass spectrometry (LC–MS) based targeted metabolomics and 16S rRNA gene sequence analysis, semi-quantitatively compared the effects of 10-day UFP exposures on obese C57B6 mouse gut microbial population, changes in diversity and community function compared to a phosphate buffer solution (PBS) control group. Our results show that sex-specific differences in the gut microbial population in response to UFP exposure can be observed, as UFPs appear to have a differential impact on several bacterial families in males and females. Meanwhile, the alteration of seventy-five metabolites from the gut microbial metabolome varied significantly (ANOVA p < 0.05) across the PBS control, B0, and B20 groups. Multivariate analyses revealed that the fuel-type specific disruption to the microbial metabolome was observed in both sexes, with stronger disruptive effects found in females in comparison to male obese mice. Metabolic signatures of bacterial cellular oxidative stress, such as the decreased concentration of nucleotides and lipids and increased concentrations of carbohydrate, energy, and vitamin metabolites were detected. Furthermore, blood metabolites from the obese mice were differentially affected by the fuel types used to generate the UFPs (B0 vs. B20).

Is perioperative antibiotic necessary in straightforward implant placement procedures?

2020 ◽  
Author(s):  
Elçin Bedeloğlu ◽  
Mustafa Yalçın ◽  
Cenker Zeki Koyuncuoğlu
Keyword(s):  
Clavulanic Acid ◽  
Dental Implant ◽  
Prophylactic Antibiotic ◽  
Antibiotic Use ◽  
Implant Failure ◽  
Control Group ◽  
Implant Placement ◽  
Significant Difference ◽  
Amoxicillin Clavulanic Acid ◽  
Experimental Group

The purpose of this non-random retrospective cohort study was to evaluate the impact of prophylactic antibiotic on early outcomes including postoperative pain, swelling, bleeding and cyanosis in patients undergoing dental implant placement before prosthetic loading. Seventy-five patients (45 males, 30 females) whose dental implant placement were completed, included to the study. Patients used prophylactic antibiotics were defined as the experimental group and those who did not, were defined as the control group. The experimental group received 2 g amoxicillin + clavulanic acid 1 h preoperatively and 1 g amoxicillin + clavulanic acid twice a day for 5 days postoperatively while the control group had received no prophylactic antibiotic therapy perioperatively. Data on pain, swelling, bleeding, cyanosis, flap dehiscence, suppuration and implant failure were analyzed on postoperative days 2, 7, and 14 and week 12. No statistically significant difference was detected between the two groups with regard to pain and swelling on postoperative days 2, 7, and 14 and week 12 ( p &gt;0.05), while the severity of pain and swelling were greater on day 2 compared to day 7 and 14 and week 12 in both groups ( p =0.001 and p &lt;0.05, respectively). Similarly, no significant difference was found between the two groups with regard to postoperative bleeding and cyanosis. Although flap dehiscence was more severe on day 7 in the experimental group, no significant difference was found between the two groups with regard to the percentage of flap dehiscence assessed at other time points. Within limitations of the study, it has been demonstrated that antibiotic use has no effect on implant failure rates in dental implant surgery with a limited number of implants. We conclude that perioperative antibiotic use may not be required in straightforward implant placement procedures. Further randomized control clinical studies with higher numbers of patients and implants are needed to substantiate our findings.

Do Children Who Experience Laryngospasm Have an Increased Risk of Upper Respiratory Tract Infection?

1996 ◽  
Vol 85 (3) ◽  
pp. 475-480. ◽  
Author(s):  
Mark S. Schreiner ◽  
Irene O'Hara ◽  
Dorothea A. Markakis ◽  
George D. Politis
Keyword(s):  
Confidence Interval ◽  
Respiratory Infection ◽  
Odds Ratio ◽  
Signs And Symptoms ◽  
Control Group ◽  
Upper Respiratory Tract ◽  
Upper Respiratory Infection ◽  
Airway Surgery ◽  
Increased Risk ◽  
Upper Respiratory

Background Laryngospasm is the most frequently reported respiratory complication associated with upper respiratory infection and general anesthesia in retrospective studies, but prospective studies have failed to demonstrate any increase in risk. Methods A case-control study was performed to examine whether children with laryngospasm were more likely to have an upper respiratory infection on the day of surgery. The parents of all patients (N = 15,183) who were admitted through the day surgery unit were asked if their child had an active or recent (within 2 weeks of surgery) upper respiratory infection and were questioned about specific signs and symptoms to determine if the child met Tait and Knight's definition of an upper respiratory infection. Control subjects were randomly selected from patients whose surgery had occurred within 1 day of the laryngospasm event. Results Patients who developed laryngospasm (N = 123) were 2.05 times (95% confidence interval 1.21-3.45) more likely to have an active upper respiratory infection as defined by their parents than the 492 patients in the control group (P &lt; or = 0.01). The development of laryngospasm was not related to Tait and Knight's definition for an upper respiratory infection or to recent upper respiratory infection. Children with laryngospasm were more likely to be younger (odds ratio = 0.92, 95% confidence interval 0.87-0.99), to be scheduled for airway surgery (odds ratio = 2.08, 95% confidence interval 1.21-3.59), and to have their anesthesia supervised by a less experienced anesthesiologist (odds ratio = 1.69, 95% confidence interval 1.04-2.7) than children in the control group. Conclusion Laryngospasm was more likely to occur in children with an active upper respiratory infection, children who were younger, children who were undergoing airway surgery, and children whose anesthesia were supervised by less experienced anesthesiologists. Understanding the risk factors and the magnitude of the likely risk should help clinicians make the decision as to whether to anesthetize children with upper respiratory infection.

scholarly journals Ratio of Klebsiella/Bifidobacterium in early life correlates with later development of paediatric allergy

2017 ◽  
Vol 8 (5) ◽  
pp. 681-695 ◽  
Author(s):  
J.S.Y. Low ◽  
S.-E. Soh ◽  
Y.K. Lee ◽  
K.Y.C. Kwek ◽  
J.D. Holbrook ◽  
...  
Keyword(s):  
Intestinal Microbiota ◽  
Allergic Disease ◽  
Early Life ◽  
16S Rrna Gene Sequencing ◽  
Early Infancy ◽  
Rrna Gene ◽  
Microbial Composition ◽  
Healthy Infants ◽  
Increased Risk ◽  
Paediatric Allergy

Several studies have reported that intestinal microbial colonisation patterns differ between non-allergic and allergic infants. However, the microbial signature underlying the pathogenesis of allergies remains unclear. We aim to gain insight into the development of the intestinal microbiota of healthy infants and infants who develop allergy in early life, and identify potential microbiota biomarkers of later allergic disease. Using a case-control design in a Chinese sub-cohort of a Singaporean birth cohort (GUSTO), we utilised 16S rRNA gene sequencing to assess intestinal microbial composition and diversity of 21 allergic and 18 healthy infants at 3 weeks, 3 months and 6 months of age, and correlated the microbiota with allergy at ages 18 and 36 months. Pronounced differences in intestinal microbiota composition between allergic and healthy infants were observed at 3 months of age. The intestine of healthy infants was colonised with higher abundance of commensal Bifidobacterium. Conversely, Klebsiella, an opportunistic pathogen, was significantly enriched in the allergic infants. Interestingly, infants with a high Klebsiella/Bifidobacterium (K/B) ratio (above the population median K/B ratio) at age 3 months had an odds ratio of developing allergy by 3 years of age of 9.00 (95% confidence interval 1.46-55.50) compared to those with low K/B ratio. This study demonstrated a relationship between the ratio of genera Klebsiella and Bifidobacterium during early infancy and development of paediatric allergy in childhood. Our study postulates that an elevated K/B ratio in early infancy could be a potential indicator of an increased risk of allergy development. This line of research might enable future intervention strategies in early life to prevent or treat allergy. Our study provides new insights into microbial signatures associated with childhood allergy, in particular, suggests that an elevated K/B ratio could be a potential early-life microbiota biomarker of allergic disease.

scholarly journals Legionella pneumophila infection and antibiotic treatment engenders a highly disturbed pulmonary microbiome with decreased microbial diversity

2019 ◽  
Author(s):  
Ana Elena Pérez-Cobas ◽  
Christophe Ginevra ◽  
Christophe Rusniok ◽  
Sophie Jarraud ◽  
Carmen Buchrieser
Keyword(s):  
Antibiotic Treatment ◽  
Legionella Pneumophila ◽  
Severe Pneumonia ◽  
Resistant Bacteria ◽  
Rrna Gene ◽  
Microbial Composition ◽  
Bacterial Composition ◽  
Lung Microbiome ◽  
The Impact ◽  
Healthy Lung

ABSTRACTBackgroundLung microbiome analyses have shown that the healthy lung is not sterile but it is colonized like other body sites by bacteria, fungi and viruses. However, little is known about the microbial composition of the lung microbiome during infectious diseases such as pneumonia and how it evolves during antibiotic therapy. To better understand the impact of the composition of the pulmonary microbiome on severity and outcome of pneumonia we analysed the composition and evolution of the human lung microbiome during pneumonia caused by the bacterium Legionella pneumophila.ResultsWe collected 10 bronchoalveolar lavage (BAL) samples from three patients during long-term hospitalisation due to severe pneumonia and performed a longitudinal in-depth study of the composition of their lung microbiome by high-throughput Illumina sequencing of the 16S rRNA gene (bacteria and archaea), ITS region (fungi) and 18S rRNA gene (eukaryotes). We found that the composition of the bacterial lung microbiome during pneumonia is hugely disturbed containing a very high percentage of the pathogen, a very low bacterial diversity, and an increased presence of opportunistic microorganisms such as species belonging to Staphylococcaceae and Streptococcaceae. The microbiome of antibiotic treated patients cured from pneumonia represented a different perturbation state with a higher abundance of resistant bacteria (mainly Firmicutes) and a significantly different bacterial composition as that found in healthy individuals. In contrast, the mycobiome remains more stable during pneumonia and antimicrobial therapy. Interestingly we identified possible cooperation within and between both communities. Furthermore, archaea (Methanobrevibacter) and protozoa (Acanthamoeba and Trichomonas) were detected.ConclusionsBacterial pneumonia leads to a collapse of the healthy microbiome and a strongly disturbed bacterial composition of the pulmonary microbiome that is dominated by the pathogen. Antibiotic treatment allows some bacteria to regrow or recolonize the lungs but the restoration of a healthy lung microbiome composition is only regained a certain time after the antibiotic treatment. Archaea and protozoa should also be considered, as they might be important but yet overseen members of the lung microbiome. Interactions between the micro- and the mycobiome might play a role in the restoration of the microbiome and the clinical evolution of the disease.

scholarly journals Inhibition of Tumor Growth by Dietary Indole-3-Carbinol in a Prostate Cancer Xenograft Model May Be Associated with Disrupted Gut Microbial Interactions

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 467 ◽  
Author(s):  
Yanbei Wu ◽  
Robert Li ◽  
Haiqiu Huang ◽  
Arnetta Fletcher ◽  
Lu Yu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Gut Microbiome ◽  
Species Interactions ◽  
Tumor Development ◽  
Xenograft Model ◽  
Microbial Interactions ◽  
Control Group ◽  
Rrna Gene ◽  
Microbial Composition

Accumulated evidence suggests that the cruciferous vegetables-derived compound indole-3-carbinol (I3C) may protect against prostate cancer, but the precise mechanisms underlying its action remain unclear. This study aimed to verify the hypothesis that the beneficial effect of dietary I3C may be due to its modulatory effect on the gut microbiome of mice. Athymic nude mice (5–7 weeks old, male, Balb c/c nu/nu) with established tumor xenografts were fed a basal diet (AIN-93) with or without 1 µmoles I3C/g for 9 weeks. The effects of dietary I3C on gut microbial composition and microbial species interactions were then examined by 16s rRNA gene-based sequencing and co-occurrence network analysis. I3C supplementation significantly inhibited tumor growth (p < 0.0001) and altered the structure of gut microbiome. The abundance of the phylum Deferribacteres, more specifically, Mucispirillum schaedleri, was significantly increased by dietary I3C. Additionally, I3C consumption also changed gut microbial co-occurrence patterns. One of the network modules in the control group, consisting of seven bacteria in family S-27, was positively correlated with tumor size (p < 0.009). Moreover, dietary I3C disrupted microbial interactions and altered this association between specific microbial network and tumor development. Our results unraveled complex relationships among I3C ingestion, gut microbiota, and prostate tumor development and may provide a novel insight into the mechanism for the chemopreventive effect of dietary I3C on prostate cancer.

scholarly journals Effect of Ceftriaxone versus Amoxicillin + Clavulanic Acid for Treatment of Acute Bacterial Rhino Sinusitis: Short Course Therapy

2018 ◽  
Vol 6 (8) ◽  
pp. 1419-1422 ◽  
Author(s):  
Malath Azeez Al-Saadi ◽  
Safaa Sahib Naji Sultan
Keyword(s):  
Clavulanic Acid ◽  
Age Groups ◽  
High Dose ◽  
Upper Respiratory Tract ◽  
Once Daily ◽  
Short Course ◽  
Gender And Age ◽  
Acute Bacterial Sinusitis ◽  
Amoxicillin Clavulanic Acid ◽  
Acute Bacterial Rhinosinusitis

BACKGROUND: Acute bacterial rhinosinusitis is one of upper respiratory tract infection that disturbs patient life and requires special consideration.AIM: To evaluate the efficiency of Ceftriaxone versus a high dose of Amoxicillin-clavulanic acid for the treatment of acute bacterial rhinosinusitis.PATIENTS AND METHOD: Observational retrospective study include120 patients of both sex classified into two groups equally conducted. G1 treated with Ceftriaxone 1 g intramuscular injection once daily while, G2 treated with oral Amoxicillin-clavulanic acid (875 mg/125 mg) twice daily for 3-4 days then, the outcome of treatment evaluated as a cure or failed at the fifth or fourth day of treatment.RESULTS: Significant cure response observed in Ceftriaxone treated patient's P ≤ 0.05 and significant failure response observed in Amoxicillin-clavulanic acid-treated patients when groups compared with each other. About gender and age groups, no significant differences in number between group 1 and 2 P ≥ 0.05.CONCLUSION: Ceftriaxone found more effective in the treatment of acute bacterial sinusitis than Amoxicillin+ clavulanic acid. Amoxicillin+clavulanic acid associated with more male failure cases recorded than female.

scholarly journals Antibiotic Resistance in Haemophilus influenzae Decreased, except for β-Lactamase-Negative Amoxicillin-Resistant Isolates, in Parallel with Community Antibiotic Consumption in Spain from 1997 to 2007

2008 ◽  
Vol 52 (8) ◽  
pp. 2760-2766 ◽  
Author(s):  
Silvia García-Cobos ◽  
José Campos ◽  
Emilia Cercenado ◽  
Federico Román ◽  
Edurne Lázaro ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Haemophilus Influenzae ◽  
Clavulanic Acid ◽  
Antimicrobial Agents ◽  
Geographic Area ◽  
Antibiotic Consumption ◽  
Control Group ◽  
Promoter Regions ◽  
Geometric Means ◽  
Amoxicillin Clavulanic Acid

ABSTRACT The susceptibility to 14 antimicrobial agents and the mechanisms of aminopenicillin resistance were studied in 197 clinical isolates of Haemophilus influenzae—109 isolated in 2007 (study group) and 88 isolated in 1997 (control group). Community antibiotic consumption trends were also examined. H. influenzae strains were consecutively isolated from the same geographic area, mostly from respiratory specimens from children and adults. Overall, amoxicillin resistance decreased by 8.4% (from 38.6 to 30.2%). β-Lactamase production decreased by 15.6% (from 33 to 17.4%, P = 0.01), but amoxicillin resistance without β-lactamase production increased by 7.1% (from 5.7 to 12.8%). All β-lactamase-positive isolates were TEM-1, but five different promoter regions were identified, with Pdel being the most prevalent in both years, and Prpt being associated with the highest amoxicillin resistance. A new promoter consisting of a double repeat of 54 bp was detected. Community consumption of most antibiotics decreased, as did the geometric means of their MICs, but amoxicillin-clavulanic acid and azithromycin consumption increased by ca. 60%. For amoxicillin-clavulanic acid, a 14.2% increase in the population with an MIC of 2 to 4 μg/ml (P = 0.02) was observed; for azithromycin, a 21.2% increase in the population with an MIC of 2 to 8 μg/ml (P = 0.0005) was observed. In both periods, the most common gBLNAR (i.e., H. influenzae isolates with mutations in the ftsI gene as previously defined) patterns were IIc and IIb. Community consumption of trimethoprim-sulfamethoxazole decreased by 54%, while resistance decreased from 50 to 34.9% (P = 0.04). Antibiotic resistance in H. influenzae decreased in Spain from 1997 to 2007, but surveillance should be maintained since new forms of resistances may be developing.

scholarly journals Analysis of Hindgut Microbiome of Sheep and Effect of Different Husbandry Conditions

Animals ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 4
Author(s):  
Giulietta Minozzi ◽  
Filippo Biscarini ◽  
Emanuela Dalla Costa ◽  
Matteo Chincarini ◽  
Nicola Ferri ◽  
...  
Keyword(s):  
Animal Health ◽  
Control Group ◽  
P Value ◽  
Rrna Gene ◽  
Microbial Composition ◽  
Core Microbiome ◽  
Fecal Microbiome ◽  
Microbiome Composition ◽  
The Core ◽  
Wide Range

The microbiome is now seen as an important resource to understand animal health and welfare in many species. However, there are few studies aiming at identifying the association between fecal microbiome composition and husbandry conditions in sheep. A wide range of stressors associated with management and housing of animals increases the hypothalamic–pituitary axis activity, with growing evidence that the microbiome composition can be modified. Therefore, the purpose of the present study was to describe the core microbiome in sheep, characterized using 16S rRNA gene sequencing, and to explore whether exposure to stressful husbandry conditions changed sheep hindgut microbiome composition. Sheep (n = 10) were divided in two groups: isolated group (individually separated for 3 h/day) and control group (housed in the home pen for the entire trial period). Sheep core microbiome was dominated by Firmicutes (43.6%), Bacteroidetes (30.38%), Proteobacteria (10.14%), and Verrucomicrobia (7.55%). Comparative results revealed few operational taxonomic units (OTUs) with significantly different relative abundance between groups. Chao1, abundance-based coverage estimator (ACE), and Fisher’s alpha indices did not show differences between groups. OTU-based Bray–Curtis distances between groups were not significant (p-value = 0.07). In conclusion, these results describing the core microbiome of sheep do not suggest a strong effect of stressful husbandry conditions on microbial composition.

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