The Continuum of Microbial Ecosystems along the Female Reproductive Tract: Implications for Health and Fertility.

The microbial ecosystem of the female urogenital tract is composed of many niche microenvironments across multiple organ systems in the urinary and reproductive tract. It is complex and contains a variety of bacteria, archaea, viruses, yeast, and protozoa-Many of which are still unidentified or whose functionality is unknown. Unlike the gut microbiome, whose composition is relatively stable in the absence of external perturbations, the urogenital microbiome is constantly shifting in response to biological cycles such as hormonal fluctuations during menstruation. Microbial composition differs between women but the dominance of some microbial families, such as Lactobacillaceae and other lactic acid-producing bacteria, are shared. Research suggests that it is difficult to define a universal healthy urogenital microbiome and consequently map a path to recovery from disease due to dysbiosis. Due to its temporal shifts, the female urogenital microbiome offers a unique opportunity to examine the biological mechanisms that work to restore a microbiome to its baseline. Common functional disorders in women's health are often difficult to diagnose and treat, are prone to recurrence, and can lead to subfertility or infertility. Knowledge of the interconnected microorganism communities along the continuum of the female reproductive tract could revolutionize the quality of women's healthcare.

Pharmacokinetics of 38 Percent Silver Diamine Fluoride in Children.

PURPOSE: The purpose of this study was to measure serum levels and characterize the pharmacokinetics of silver and fluoride in healthy children receiving silver diamine fluoride (SDF) treatment for dental caries lesions. METHODS: Children (three to 13 years old with at least one caries lesion) were recruited at the University of California, San Francisco Pediatric Dental Clinic from August 2019 through March 2020. Blood was obtained at one randomly selected timepoint up to 168 hours after SDF application. Serum fluoride and silver were measured, and population pharmacokinetic modeling was used to estimate pharmacokinetic parameters and simulate silver concentration versus time profiles in cohorts of children (15 to 50 kg). RESULTS: Fifty-five children completed the study. Serum fluoride had no discernable temporal pattern. Silver concentra- tions were best described by a one-compartment model with first-order absorption and elimination, and weight as a covariate. Simulated 15 kg children had higher predicted peak silver concentrations than simulated 50 kg children (22.0 ng/mL [95 percent confidence interval {95 percent CI} equals 19.4 to 24.6] versus 12.8 ng/mL [95 percent CI equals 11.3 to 14.3]), and a longer predicted silver half-life (15.5 days [95 percent CI equals 12.5 to 18.5] versus 4.0 days [95 percent CI equals 2.7 to 5.3]). CONCLUSIONS: Evidence presented indicate that topical silver diamine fluoride application in children is safe, and serum concentrations of fluoride and silver pose little risk of toxicity.

Nutrition, Immunosenescence, and Infectious Disease: An Overview of the Scientific Evidence on Micronutrients and on Modulation of the Gut Microbiota.

The immune system is key to host defense against pathogenic organisms. Aging is associated with changes in the immune system, with a decline in protective components (immunosenescence), increasing susceptibility to infectious disease, and a chronic elevation in low-grade inflammation (inflammaging), increasing the risk of multiple noncommunicable diseases. Nutrition is a determinant of immune cell function and of the gut microbiota. In turn, the gut microbiota shapes and controls the immune and inflammatory responses. Many older people show changes in the gut microbiota. Age-related changes in immune competence, low-grade inflammation, and gut dysbiosis may be interlinked and may relate, at least in part, to age-related changes in nutrition. A number of micronutrients (vitamins C, D, and E and zinc and selenium) play roles in supporting the function of many immune cell types. Some trials report that providing these micronutrients as individual supplements can reverse immune deficits in older people and/or in those with insufficient intakes. There is inconsistent evidence that this will reduce the risk or severity of infections including respiratory infections. Probiotic, prebiotic, or synbiotic strategies that modulate the gut microbiota, especially by promoting the colonization of lactobacilli and bifidobacteria, have been demonstrated to modulate some immune and inflammatory biomarkers in older people and, in some cases, to reduce the risk and severity of gastrointestinal and respiratory infections, although, again, the evidence is inconsistent. Further research with well-designed and well-powered trials in at-risk older populations is required to be more certain about the role of micronutrients and of strategies that modify the gut microbiota-host relationship in protecting against infection, especially respiratory infection.

Sources of Interindividual Variability.

The efficacy, safety, and tolerability of drugs are dependent on numerous factors that influence their disposition. A dose that is efficacious and safe for one individual may result in sub-therapeutic or toxic blood concentrations in others. A significant source of this variability in drug response is drug metabolism, where differences in presystemic and systemic biotransformation efficiency result in variable degrees of systemic exposure (e.g., AUC, Cmax, and/or Cmin) following administration of a fixed dose.Interindividual differences in drug biotransformation have been studied extensively. It is recognized that both intrinsic factors (e.g., genetics, age, sex, and disease states) and extrinsic factors (e.g., diet , chemical exposures from the environment, and the microbiome) play a significant role. For drug-metabolizing enzymes, genetic variation can result in the complete absence or enhanced expression of a functional enzyme. In addition, upregulation and downregulation of gene expression, in response to an altered cellular environment, can achieve the same range of metabolic function (phenotype), but often in a less predictable and time-dependent manner. Understanding the mechanistic basis for variability in drug disposition and response is essential if we are to move beyond the era of empirical, trial-and-error dose selection and into an age of personalized medicine that will improve outcomes in maintaining health and treating disease.

Analysis of the metabolome of Anopheles gambiae mosquito after exposure to Mycobacterium ulcerans.

Infection with Mycobacterium ulcerans causes Buruli Ulcer, a neglected tropical disease. Mosquito vectors are suspected to participate in the transmission and environmental maintenance of the bacterium. However, mechanisms and consequences of mosquito contamination by M. ulcerans are not well understood. We evaluated the metabolome of the Anopheles gambiae mosquito to profile the metabolic changes associated with bacterial colonization. Contamination of mosquitoes with live M. ulcerans bacilli results in disruptions to lipid metabolic pathways of the mosquito, specifically the utilization of glycerolipid molecules, an affect that was not observed in mosquitoes exposed to dead M. ulcerans. These results are consistent with aberrations of lipid metabolism described in other mycobacterial infections, implying global host-pathogen interactions shared across diverse saprophytic and pathogenic mycobacterial species. This study implicates features of the bacterium, such as the putative M. ulcerans encoded phospholipase enzyme, which promote virulence, survival, and active adaptation in concert with mosquito development, and provides significant groundwork for enhanced studies of the vector-pathogen interactions using metabolomics profiling. Lastly, metabolic and survival data suggest an interaction which is unlikely to contribute to transmission of M. ulcerans by A. gambiae and more likely to contribute to persistence of M. ulcerans in waters cohabitated by both organisms.