Evaluation of the effect of tyrothricin on beta-hemolytic streptococci in salva. Part I: The effect of salvia upon bacteria. Part II: Effect of tyrothricin on the New York 5 strain of Streptococcus pyogenes in saliva

Part II of thesis by Brancato, Noyes, and Swift. Part I of thesis by Swift. Thesis (M.A.)--Boston UniversityThe antibacterial effect of saliva has been known for many years. Still the exact nature of the antagonistic action of saliva upon bacteria is as yet unsettled. Most workers agree, however, that the salivary bacterial inhibitory action is brought about in at least six ways: The first antibacterial effect is changes in pH, which affect the growth of oral organisms. Furthermore, this change in pH is dependent on diet and on the type of organisms in the oral cavity. The second is the mechanical factors involved, for saliva not only flushes bacteria from the mouth, but dilutes the number of organisms as well. The third is the antibacterial action of the cellular components in saliva. The leukocytes in saliva have a phagocytic action, and the non-phagocytic epithelial cells slough off in sheets, carrying with them thousands of organisms which have lodged in the partially turned edges of the necrotic cells . The fourth antibacterial action is ascribed to the presence of immune bodies in the saliva which lyse or agglutinate the oral bacteria. The fifth is the presence of oral bacteria which are antagonistic to new invaders. And the sixth is the presence of enzymes that lyse some oral bacteria or alter their cell membranes thereby inhibiting further growth. In recent years a great deal of investigation has been made to ascribe the enzymatic effect as the chief antibacterial agent in saliva; however, contradictory work has been done to try to attribute the chief antibacterial action of salivary cocci. Indeed the antibacterial effect of saliva is not always present, for the bacteriostatic effect of saliva is variable from day to day and from individual to individual. The only way of reducing the number of oral bacteria is to add to the saliva an antibiotic. Tyrothricin was used. In an attempt to delineate the range of concentration of tyrothricin per ml. effective against the New York 5 strain of Streptococcus pryogenes in saliva, this experiment was carried out. It was molded after the unpublished work of Belding concerning the effect of tyrothricin on the Oxford Strain of Staphylococcus aureus in saliva. The required inoculum of approximately one million organisms per ml was obtained by growing cultures of the streptococci under uniform conditions and setting up a table of the absorbances and viable cell counts, from which dilution factors for further cultures could be estimated. Controls were set up for determining possible inhibition of tyrothricin and/or test organisms by the various diluting fluids including saliva. Final concentrations per ml of 10, 25, 50, 75, and 100 µg of tyrothricin integrated with saliva and an approximated number of streptococci were plated out after 30 and 60 minutes exposure periods and were counted after 24 and 48 hours of incubation at 37°C. Whereas 1 µg per ml of tyrothricin reduced markedly the number of streptococci suspended in water during a 30 minute exposure period and 10 µg per ml, under similar conditions, caused complete inhibition, 10 µg per ml of the antibiotic was ineffective against this test organism suspended in saliva during a 30 minute exposure period but caused about an 80 per cent reduction in viable organisms during 60 minutes exposure. The length of the exposure period necessary for effective inhibition varied inversely with the concentration of tyrothricin per ml, 100 µg per ml causing a 98 per cent reduction of viable organisms during an exposure period of 1 minute. For the 30 minute exposure period, the quantity of tyrothricin effective against this strain of streptococci mixed in saliva would fall in the 10 µg - 25 µg per ml range and for shorter exposure periods, the concentration per ml would have to be greater. Cultures completely negative during 24 hours incubation at 37°C, showed a typical growth during 48 hours. This is considered indicative of the bacteriostatic action of tyrothricin which, prolonged, resulted in the death of large numbers of the streptococci. The results which were obtained in these experiments serve chiefly to point out the way for further work and to form a basis for the general conclusions listed below: 1. The action of tyrothricin on bacteria is inhibited by saliva to a large degree. 2. The minimal amounts of tyrothricin necessary to produce complete inhibition of growth of Streptococcus pyogenes in saliva is between 25 and 50 µg per ml acting for 30 minutes. 3. There is an effective reduction of Streptococcus pyogenes in saliva by concentrations of tyrothricin between 10 and 25 µg per ml acting for 30 minutes. 4. Tyrothricin acts immediately upon contact with Streptococcus pyogenes. 5. The action of tyrothricin on Streptococcus pyogenes in saliva is apparently bacteriostatic and not of a permanent nature as manifested by growth of atypical colonies during 48 hours incubation. 6. Tyrothricin above a concentration of 50 µg per ml had a definite reducing effect on the bacterial population of this saliva. 7. Saliva also has a bactericidal or bacteriostatic (or both) action against Streptococcus pyogenes

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease

Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma.

Concentrations of liver enzymes in plasma are widely used as indicators of liver disease. We carried out a genome-wide association study in 61,089 individuals, identifying 42 loci associated with concentrations of liver enzymes in plasma, of which 32 are new associations (P = 10(-8) to P = 10(-190)). We used functional genomic approaches including metabonomic profiling and gene expression analyses to identify probable candidate genes at these regions. We identified 69 candidate genes, including genes involved in biliary transport (ATP8B1 and ABCB11), glucose, carbohydrate and lipid metabolism (FADS1, FADS2, GCKR, JMJD1C, HNF1A, MLXIPL, PNPLA3, PPP1R3B, SLC2A2 and TRIB1), glycoprotein biosynthesis and cell surface glycobiology (ABO, ASGR1, FUT2, GPLD1 and ST3GAL4), inflammation and immunity (CD276, CDH6, GCKR, HNF1A, HPR, ITGA1, RORA and STAT4) and glutathione metabolism (GSTT1, GSTT2 and GGT), as well as several genes of uncertain or unknown function (including ABHD12, EFHD1, EFNA1, EPHA2, MICAL3 and ZNF827). Our results provide new insight into genetic mechanisms and pathways influencing markers of liver function