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(1) Background: The rise in electronic cigarette (E-cigarette) popularity, especially among adolescents, has prompted research to investigate potential effects on health. Although much research has been carried out on the effect on lung health, the first site exposed to vaping-the oral cavity-has received relatively little attention. The aims of this study were twofold: to examine the effects of E-liquids on the viability and hydrophobicity of oral commensal streptococci, and the effects of E-cigarette-generated aerosols on the biomass and viability of oral commensal streptococci. (2) Methods: Quantitative and confocal biofilm analysis, live-dead staining, and hydrophobicity assays were used to determine the effect on oral commensal streptococci after exposure to E-liquids and/or E-cigarette-generated aerosols. (3) Results: E-liquids and flavors have a bactericidal effect on multispecies oral commensal biofilms and increase the hydrophobicity of oral commensal streptococci. Flavorless and some flavored E-liquid aerosols have a bactericidal effect on oral commensal biofilms while having no effect on overall biomass. (4) Conclusions: These results indicate that E-liquids/E-cigarette-generated aerosols alter the chemical interactions and viability of oral commensal streptococci. Consequently, the use of E-cigarettes has the potential to alter the status of disease and health in the oral cavity and, by extension, affect systemic health.

There is currently no suitable autologous tissue to bridge large tracheal defects. As a result, no standard of care exists for long-segment tracheal reconstruction. Tissue engineering has the potential to create a scaffold from allografts or xenografts that can support neotissue regeneration identical to the native trachea. Recent advances in tissue engineering have led to the idea of partial decellularization that allows for the creation of tracheal scaffolds that supports tracheal epithelial formation while preserving mechanical properties. However, the ability of partial decellularization to eliminate graft immunogenicity remains unknown, and understanding the immunogenic properties of partially decellularized tracheal grafts (PDTG) is a critical step toward clinical translation. Here, we determined that tracheal allograft immunogenicity results in epithelial cell sloughing and replacement with dysplastic columnar epithelium and that partial decellularization creates grafts that are able to support an epithelium without histologic signs of rejection. Moreover, allograft implantation elicits CD8+ T-cell infiltration, a mediator of rejection, while PDTG did not. Hence, we establish that partial decellularization eliminates allograft immunogenicity while creating a scaffold for implantation that can support spatially appropriate airway regeneration., Competing Interests: The authors have no conflicts of interest to disclose as described by the American Journal of Transplantation., (© 2023 The Authors. Bioengineering & Translational Medicine published by Wiley Periodicals LLC on behalf of The American Institute of Chemical Engineers.)

An understanding of the changes in gut microbiome composition and its associated metabolic functions is important to assess the potential implications thereof on host health. Thus, to elucidate the connection between the gut microbiome and the fecal and plasma metabolomes, two poorly bioavailable carbapenem antibiotics (doripenem and meropenem), were administered in a 28-day oral study to male and female Wistar rats. Additionally, the recovery of the gut microbiome and metabolomes in doripenem-exposed rats were studied one and two weeks after antibiotic treatment (i.e., doripenem-recovery groups). The 16S bacterial community analysis revealed an altered microbial population in all antibiotic treatments and a recovery of bacterial diversity in the doripenem-recovery groups. A similar pattern was observed in the fecal metabolomes of treated animals. In the recovery group, particularly after one week, an over-compensation was observed in fecal metabolites, as they were significantly changed in the opposite direction compared to previously changed metabolites upon 28 days of antibiotic exposure. Key plasma metabolites known to be diagnostic of antibiotic-induced microbial shifts, including indole derivatives, hippuric acid, and bile acids were also affected by the two carbapenems. Moreover, a unique increase in the levels of indole-3-acetic acid in plasma following meropenem treatment was observed. As was observed for the fecal metabolome, an overcompensation of plasma metabolites was observed in the recovery group. The data from this study provides insights into the connectivity of the microbiome and fecal and plasma metabolomes and demonstrates restoration post-antibiotic treatment not only for the microbiome but also for the metabolomes. The importance of overcompensation reactions for health needs further studies.

To elucidate if artificial sweeteners modify fecal bacterial composition and the fecal and plasma metabolomes, Wistar rats from both sexes were treated for 28 days with acesulfame potassium (40 and 120 mg/kg body weight) and saccharin (20 and 100 mg/kg body weight). Targeted MS-based metabolome profiling (plasma and feces) and fecal 16S gene sequencing were conducted. Both sweeteners exhibited only minor effects on the fecal metabolome and microbiota. Saccharin treatment significantly altered amino acids, lipids, energy metabolism and specifically, bile acids in the plasma metabolome. Additionally, sex-specific differences were observed for conjugated primary and secondary bile acids. Acesulfame potassium treated male rats showed larger alterations in glycine conjugated primary and secondary bile-acids than females. Other changes in the plasma metabolome were more profound for saccharin than acesulfame potassium, for both sexes. Changes in conjugated bile-acids in plasma, which are often associated with microbiome changes, and the absence of similarly large changes in microbiota suggest an adaptative change of the latter, rather than toxicity. Further studies with a high resolution 16S sequencing data and/or metagenomics approach, with particular emphasis on bile acids, will be required to explore the mechanisms driving this metabolic outcome of saccharin in Wistar rats., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The oral uptake of nanoparticles is an important route of human exposure and requires solid models for hazard assessment. While the systemic availability is generally low, ingestion may not only affect gastrointestinal tissues but also intestinal microbes. The gut microbiota contributes essentially to human health, whereas gut microbial dysbiosis is known to promote several intestinal and extra-intestinal diseases. Gut microbiota-derived metabolites, which are found in the blood stream, serve as key molecular mediators of host metabolism and immunity., Results: Gut microbiota and the plasma metabolome were analyzed in male Wistar rats receiving either SiO 2 (1000 mg/kg body weight/day) or Ag nanoparticles (100 mg/kg body weight/day) during a 28-day oral gavage study. Comprehensive clinical, histopathological and hematological examinations showed no signs of nanoparticle-induced toxicity. In contrast, the gut microbiota was affected by both nanoparticles, with significant alterations at all analyzed taxonomical levels. Treatments with each of the nanoparticles led to an increased abundance of Prevotellaceae, a family with gut species known to be correlated with intestinal inflammation. Only in Ag nanoparticle-exposed animals, Akkermansia, a genus known for its protective impact on the intestinal barrier was depleted to hardly detectable levels. In SiO 2 nanoparticles-treated animals, several genera were significantly reduced, including probiotics such as Enterococcus. From the analysis of 231 plasma metabolites, we found 18 metabolites to be significantly altered in Ag-or SiO 2 nanoparticles-treated rats. For most of these metabolites, an association with gut microbiota has been reported previously. Strikingly, both nanoparticle-treatments led to a significant reduction of gut microbiota-derived indole-3-acetic acid in plasma. This ligand of the arylhydrocarbon receptor is critical for regulating immunity, stem cell maintenance, cellular differentiation and xenobiotic-metabolizing enzymes., Conclusions: The combined profiling of intestinal microbiome and plasma metabolome may serve as an early and sensitive indicator of gut microbiome changes induced by orally administered nanoparticles; this will help to recognize potential adverse effects of these changes to the host., (© 2022. The Author(s).)

Autism spectrum disorder (ASD) manifests sensory and perceptual atypicalities. Recent theories suggest that these may reflect a reduced influence of prior information in ASD. Some studies have found reduced adaptation to recent sensory stimuli in ASD. However, the effects of prior stimuli and prior perceptual choices can counteract one-another. Here, we investigated this using two different tasks (in two different cohorts): (i) visual location discrimination and (ii) multisensory (visual-vestibular) heading discrimination. We fit the data using a logistic regression model to dissociate the specific effects of prior stimuli and prior choices. In both tasks, perceptual decisions were biased toward recent choices. Notably, the 'attractive' effect of prior choices was significantly larger in ASD (in both tasks and cohorts), while there was no difference in the influence of prior stimuli. These results challenge theories of reduced priors in ASD, and rather suggest an increased consistency bias for perceptual decisions in ASD., Competing Interests: HF, SS, DZ, AZ No competing interests declared, (© 2021, Feigin et al.)

Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response.

Hydroxychloroquine has been touted as a potential COVID-19 treatment. Tocilizumab, an inhibitor of IL-6, has also been proposed as a treatment of critically ill patients. In this retrospective observational cohort study drawn from electronic health records we sought to describe the association between mortality and hydroxychloroquine or tocilizumab therapy among hospitalized COVID-19 patients. Patients were hospitalized at a 13-hospital network spanning New Jersey USA between March 1, 2020 and April 22, 2020 with positive polymerase chain reaction results for SARS-CoV-2. Follow up was through May 5, 2020. Among 2512 hospitalized patients with COVID-19 there have been 547 deaths (22%), 1539 (61%) discharges and 426 (17%) remain hospitalized. 1914 (76%) received at least one dose of hydroxychloroquine and 1473 (59%) received hydroxychloroquine with azithromycin. After adjusting for imbalances via propensity modeling, compared to receiving neither drug, there were no significant differences in associated mortality for patients receiving any hydroxychloroquine during the hospitalization (HR, 0.99 [95% CI, 0.80-1.22]), hydroxychloroquine alone (HR, 1.02 [95% CI, 0.83-1.27]), or hydroxychloroquine with azithromycin (HR, 0.98 [95% CI, 0.75-1.28]). The 30-day unadjusted mortality for patients receiving hydroxychloroquine alone, azithromycin alone, the combination or neither drug was 25%, 20%, 18%, and 20%, respectively. Among 547 evaluable ICU patients, including 134 receiving tocilizumab in the ICU, an exploratory analysis found a trend towards an improved survival association with tocilizumab treatment (adjusted HR, 0.76 [95% CI, 0.57-1.00]), with 30 day unadjusted mortality with and without tocilizumab of 46% versus 56%. This observational cohort study suggests hydroxychloroquine, either alone or in combination with azithromycin, was not associated with a survival benefit among hospitalized COVID-19 patients. Tocilizumab demonstrated a trend association towards reduced mortality among ICU patients. Our findings are limited to hospitalized patients and must be interpreted with caution while awaiting results of randomized trials. Trial Registration: Clinicaltrials.gov Identifier: NCT04347993., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: DAB, SMB, and NSB are employed by Berry Consultants LLC which provided statistical support for the study. EH, AHG, ALP, SM, and SLG are employed or have ownership interest in COTA Inc which provided statistical support for the study. AHG discloses consulting fees from Physicians’ Education Resource, LLC for his contributions to COVID-19 and Cancer Care. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Various environmental factors can alter the gut microbiome's composition and functionality, and modulate host health. In this study, the effects of oral and parenteral administration of two poorly bioavailable antibiotics (i.e., vancomycin and streptomycin) on male Wistar Crl/Wi(Han) rats for 28 days were compared to distinguish between microbiome-derived or -associated and systemic changes in the plasma metabolome. The resulting changes in the plasma metabolome were compared to the effects of a third reference compound, roxithromycin, which is readily bioavailable. A community analysis revealed that the oral administration of vancomycin and roxithromycin in particular leads to an altered microbial population. Antibiotic-induced changes depending on the administration routes were observed in plasma metabolite levels. Indole-3-acetic acid (IAA) and hippuric acid (HA) were identified as key metabolites of microbiome modulation, with HA being the most sensitive. Even though large variations in the plasma bile acid pool between and within rats were observed, the change in microbiome community was observed to alter the composition of the bile acid pool, especially by an accumulation of taurine-conjugated primary bile acids. In-depth investigation of the relationship between microbiome variability and their functionality, with emphasis on the bile acid pool, will be necessary to better assess the potential adverseness of environmentally induced microbiome changes.

We study the hypergeometric functions associated to five one-parameter deformations of Delsarte K3 quartic hypersurfaces in projective space. We compute all of their Picard-Fuchs differential equations; we count points using Gauss sums and rewrite this in terms of finite-field hypergeometric sums; then we match up each differential equation to a factor of the zeta function, and we write this in terms of global L -functions. This computation gives a complete, explicit description of the motives for these pencils in terms of hypergeometric motives., (© The Author(s) 2020.)

Sensitivity to stress has long been implicated in the pathogenesis of schizophrenia. It remains unclear, however, which exact mechanisms underlie the progression from vulnerability to psychotic breakdown. For the present study, we hypothesized that the induction of stress would aggravate cognitive biases in schizophrenia. A total of 20 acute and remitted schizophrenia patients and 15 healthy controls were tested with parallel versions of cognitive biases paradigms under 2 laboratory conditions: stress (loud noise, 75 dB) vs no-stress. In the course of both conditions, participants had to fill out a questionnaire that assessed depressive, obsessive-compulsive, and paranoid symptoms. For the patients with acute psychotic symptoms, paranoid but not other psychiatric symptoms were elevated under stress in comparison with no-stress. In contrast, stress somewhat diminished subclinical paranoid symptoms in healthy participants. Jumping to conclusions was evident in schizophrenia under both conditions but significantly more pronounced when stress was applied first in the acute group. A tendency emerged in both acute and remitted patients to attribute events to other people under stress which was not seen in healthy subjects. The present study may serve as a starting point for further research investigating how stress translates vulnerability into acute paranoia and to pinpoint cognitive risk factors that can be modified by treatment.

The adrenal gland comprises two endocrine tissues of distinct origin, the catecholamine-producing medulla and the steroid-producing cortex. The inner adrenocortical zone, which is in direct contact with the adrenomedullary chromaffin cells, produces dehydroepiandrostendione (DHEA) and DHEA sulfate (DHEAS). These two androgens exhibit potential effects on neurogenesis, neuronal survival, and neuronal stem cell proliferation. Unlike the closely related sympathetic neurons, chromaffin cells are able to proliferate throughout life. The aim of this study was to investigate the effect of DHEA and DHEAS on proliferation of bovine chromaffin cells from young and adult animals. We demonstrated that graded concentrations of leukemia inhibitory factor induced proliferation of chromaffin cells from young animals, whereas EGF had no effect. On the contrary, EGF increased the cell proliferation in cells from adult animals, whereas leukemia inhibitory factor was inactive. In both cases, DHEA decreased the proliferative effect induced by the growth factors. Surprisingly, DHEAS enhanced, in a dose-dependent-manner, the effect of growth factors on proliferation in cells from adult animals but not from young animals. Flutamide, ICI 182,780, and RU 486 had no effect on the action of DHEA or DHEAS on chromaffin cell proliferation. These data show that DHEA and its sulfated form, DHEAS, differentially regulate growth-factor-induced proliferation of bovine chromaffin cells. In addition, the sensitivity of chromaffin cells to different growth factors is age-dependent. Furthermore, these two androgens may act through a receptor other than the classical steroid receptors.

Limited data support the use of first-generation antihistamines for treatment of the common cold. The purpose of this study was to test the effectiveness of clemastine fumarate, a first-generation antihistamine, for treatment of sneezing and rhinorrhea associated with naturally occurring common colds. Four hundred three subjects (202 clemastine fumarate recipients and 201 placebo recipients) who reported new onset (< 24 hours) of cold symptoms that included rhinorrhea or sneezing were studied. At baseline (day 1), the mean symptom-severity scores +/- SEM for the clemastine fumarate and placebo groups were not significantly different. The mean rhinorrhea-severity score +/- SEM was not different on day 2; however, on day 3, the mean rhinorrhea-severity score +/- SEM was 1.02 +/- 0.07 for the clemastine fumarate group and 1.39 +/- 0.07 for the placebo group (P < .001). This treatment effect persisted on day 4. A significant effect on sneezing was noted on days 2-4. Sedation occurred in 14% of the clemastine fumarate-treated subjects and 1.5% of the placebo-treated subjects (P < .0001).

Toxic shock syndrome is a multisystem illness frequently complicated by hypocalcemia. The etiology of the hypocalcemia, which may be severe, is not well understood. We report two cases of fatal toxic shock syndrome accompanied by severe hypocalcemia; each patient also had an inappropriately elevated serum calcitonin level, which in one case was as high as 179,000 pg/mL. Hypercalcitoninemia may be a cause of the low serum calcium levels as well as of certain clinical manifestations of toxic shock syndrome.

We performed two studies to determine the dose-related tolerance and the efficacy of recombinant beta serine interferon (rIFN-beta ser) in experimental rhinovirus infection. In the tolerance study, 120 healthy adults received intranasal sprays of rIFN-beta ser or placebo daily for 25 d. No differences in nasal symptoms were found. Rhinoscopy detected more mucosal bleeding sites in high-dose (38%) versus low-dose (12.5%) or placebo (12.5%) recipients. There were more subepithelial lymphocytes in nasal biopsy specimens in the high-dose (54%) than the low-dose (17%) or placebo (17%) groups. In the efficacy study, 34 volunteers received daily nasal drops of IFN, beginning 36 h before challenge and for three days afterwards. The numbers of infections and days of shedding of virus were not reduced, but colds occurred less often in the high-dose (25%) than in the low-dose (55%) or placebo (64%) recipients. Nasal mucus weights were lower in the high-dose (mean +/- SD g per five days; 5 +/- 4) than placebo (31 +/- 37) recipients. Thus, rIFN-beta ser may have a more favorable therapeutic ratio than do previously tested alpha interferons.

Two randomized, double-blind, placebo-controlled trials during early autumn of 1986 and 1987 evaluated the efficacy and tolerance of recombinant interferon-beta serine (rIFN-beta ser) nasal drops for prevention of natural rhinovirus colds. In 1986, 9 X 10(6) units of rIFN-beta ser (139 subjects) or placebo (157) were administered once daily except Sundays for 4 w. Rhinovirus colds occurred in 2.8% of rIFN-beta ser recipients and 6.0% of placebo recipients during the treatment period (52% reduction, P = .3). In 1987, 24 X 10(6) units of rIFN-beta ser (186) or placebo (197) were given daily for 25 consecutive days. Rhinovirus colds developed in 6.3% of rIFN-beta ser recipients and 5.3% of placebo recipients. In each study, illness frequency and number of days with subjective colds did not differ between the groups. Recipients of nasal drops of rIFN-beta ser at either dosage did not differ in tolerance from placebo recipients. The lack of both prophylactic efficacy and nasal toxicity are in contrast to prior observations with nasal sprays of rIFN-alpha 2b.

Salmonella bacteremia is being identified with increasing frequency in persons infected with the human immunodeficiency virus. Salmonellosis may occur in patients with an established diagnosis of acquired immunodeficiency syndrome (AIDS), or it may be the first manifestation of this disorder. In patients with AIDS, salmonellosis is characterized by recurrent bacteremia despite treatment and a relative paucity of gastrointestinal manifestations. Treatment regimens may be limited by antimicrobial resistance, poor penetration of antibiotics into phagocytes, and drug intolerance; optimal therapy remains to be established. Possible mechanisms to account for this increased frequency and severity of salmonellosis include altered cell-mediated immunity, hemolysis, prior use of antibiotics, and increased exposure to the pathogen. Salmonellae should be considered among the pathogens associated with human immunodeficiency virus infection.

The clinical manifestations and circumstances of bee sting anaphylaxis have been studied retrospectively in 98 subjects. Most reactions occurred in children but the most severe reactions were seen in adult males, of whom 7 lost consciousness and 2 required cardiopulmonary resuscitation. Most stings causing anaphylaxis occurred on the unprotected feet whilst the subject was on lawn in the afternoons in December, January and February when the maximum daily temperature was between 20 and 30 degrees C. This is the temperature range when bees are particularly active in gathering pollen. However, a significantly greater frequency of anaphylactic reactions occurred at higher temperatures when bees are less active, suggesting that high environmental temperature may predispose the individual to greater exposure to bees or possibly to anaphylactic reactions per se. The presence of atopy did not appear to predispose subjects to bee venom hypersensitivity. Considerable anxiety and lifestyle alteration were identified in some subjects. The alleviation of this anxiety is considered an appropriate indication for bee venom immunotherapy.

The pathogenesis of symptoms of the common cold and their optimal treatment are incompletely understood. To evaluate the role of an oral alpha agonist alone and in combination with a nonsteroidal anti-inflammatory drug in the treatment of experimental rhinovirus colds, 58 subjects were randomized to receive pseudoephedrine 60 mg alone, pseudoephedrine 60 mg plus ibuprofen 200 mg, or placebo, four times daily for 4 1/2 days beginning 30 hours after intranasal rhinovirus inoculation under double-blind conditions. The frequencies of infection, colds occurrence, and viral shedding did not differ significantly between the groups. Total symptom scores were reduced by 59% by pseudoephedrine plus ibuprofen (p less than 0.05) and 48% by pseudoephedrine alone compared with placebo. Nasal symptom scores tended to be lower in recipients of pseudoephedrine plus ibuprofen compared with pseudoephedrine alone (p = 0.09), but other parameters showed no significant treatment differences between the groups. Rhinorrhea, as determined by nasal secretion weights, was significantly reduced in both treatment groups compared to placebo. Nasal patency measurements tended to show the greatest improvement in recipients of pseudoephedrine plus ibuprofen. Therapy was clinically well tolerated. The results suggest that an oral alpha agonist is effective in modifying certain manifestations of experimental rhinovirus infection and that the addition of a nonsteroidal anti-inflammatory drug may provide additional benefit in nasal symptoms and patency. Studies involving large numbers of patients with natural colds are needed to determine the clinical significance of these findings.