First Phase 1 Double-Blind, Placebo-Controlled, Randomized Rectal Microbicide Trial Using UC781 Gel with a Novel Index of Ex Vivo Efficacy

Objectives: Successful control of the HIV/AIDS pandemic requires reduction of HIV-1 transmission at sexually-exposed mucosae. No prevention studies of the higher-risk rectal compartment exist. We report the first-in-field Phase 1 trial of a rectally-applied, vaginally-formulated microbicide gel with the RT-inhibitor UC781 measuring clinical and mucosal safety, acceptability and plasma drug levels. A first-in-Phase 1 assessment of preliminary pharmacodynamics was included by measuring changes in ex vivo HIV-1 suppression in rectal biopsy tissue after exposure to product in vivo. Methods: HIV-1 seronegative, sexually-abstinent men and women (N = 36) were randomized in a double-blind, placebo-controlled trial comparing UC781 gel at two concentrations (0.1%, 0.25%) with placebo gel (1:1:1). Baseline, single-dose exposure and a separate, 7-day at-home dosing were assessed. Safety and acceptability were primary endpoints. Changes in colorectal mucosal markers and UC781 plasma drug levels were secondary endpoints; ex vivo biopsy infectibility was an ancillary endpoint. Results: All 36 subjects enrolled completed the 7-14 week trial (100% retention) including 3 flexible sigmoidoscopies, each with 28 biopsies (14 at 10 cm; 14 at 30 cm). There were 81 Grade 1 adverse events (AEs) and 8 Grade 2; no Grade 3, 4 or procedure-related AEs were reported. Acceptability was high, including likelihood of future use. No changes in mucosal immunoinflammatory markers were identified. Plasma levels of UC781 were not detected. Ex vivo infection of biopsies using two titers of HIV-1 BaL showed marked suppression of p24 in tissues exposed in vivo to 0.25% UC781; strong trends of suppression were seen with the lower 0.1% UC781 concentration. Conclusions: Single and 7-day topical rectal exposure to both concentrations of UC781 were safe with no significant AEs, high acceptability, no detected plasma drug levels and no significant mucosal changes. Ex vivo biopsy infections demonstrated marked suppression of HIV infectibility, identifying a potential early biomarker of efficacy. (Registered at ClinicalTrials.gov; #NCT00408538). © 2011 Anton et al

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Gas-phase specific reactivity of isomeric 1,3-benzodithiole anions: Tandem mass spectrometry and DFT theoretical studies

1,3-Benzodithiole dideuterated at the dithioacetal carbon atom has been ionized in the chemical ionization source of a tandem triple quadrupole mass spectrometer under NICI condition. Two isomeric anions are formed by abstraction of an o-phenylic proton or through abstraction of a deuteron. The fragmentation patterns occurring under dissociative collisions differ and confirm the coexistence of two nonconverting carbanions. DFT calculations show that the dithioacetal anion is more stable than the phenylic. The nucleophilic reactivity toward CS2 has been studied by collision-induced reactions in the collision cell of the tandem instrument. Both isomeric anion forms display characteristic fragmentations of the resulting [(M-H(D)) + CS2] adduct anions, demonstrating a difference in reactivity: the dithioacetal anion reacts regioselectively at C and the o-phenylic at S, DFT calculations, performed with the aim of rationalizing this observed difference and understanding the formation of the diagnostic fragments, have been successful

Gas phase reaction of neutral carbon disulfide with its hydride adduct anions: Tandem mass spectrometry and theoretical studies

In a chemical ionization source with CH4/N2O, carbon disulfide (CS2) yields its radical anion by electron capture and CHS2- by hydride attachment, By combining tandem mass spectrometric experiments and theoretical ab initio calculations, we demonstrate that hydride attachment can yield either thioformate anion or thiohydroxythiocarbonyl carbanion without interconversion. The thioformate anion reacts with neutral at CS2 carbon, whereas the syn thiohydroxythiocarbonyl carbanion attacks at the sulfur site to ultimately form HSCS2- and CS species

Systematic review of international guidelines for perioperative antibiotic prophylaxis in Head & Neck Surgery. A YO‐IFOS Head & Neck Study Group Position Paper

BACKGROUND: Surgical site infection (SSI) is defined as an infection that occurs after a surgical incision or organ manipulation during surgery. The frequency reported for clean head and neck surgical procedures without antimicrobial prophylaxis is <1%. In contrast, infection rates in patients undergoing complicated cancer surgery are high, ranging from 24% to 87% of patients without antimicrobial prophylaxis. METHODS: Guidelines and recommendations about the use of antibiotics in head and neck surgery from 2004 to 2019 were reviewed. RESULTS: Four guidelines from Oceania, 5 from South America, 5 from North America, 2 from the United Kingdom, 11 from Europe, 1 from Africa, 1 from the Middle East, and 3 from Asia were included. A total of 118 papers were included for analysis and recommendation. CONCLUSION: Antibiotic prophylaxis can decrease the incidence of SSI. However, the risks associated with antibiotic exposure and the risk of antibiotic resistance need to be taken into consideration