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Iatrogenic injury of the ureters is a feared complication of abdominal surgery. Zwitterionic near-infrared fluorophores are molecules with geometrically-balanced, electrically-neutral surface charge, which leads to renal-exclusive clearance and ultralow non-specific background binding. Such molecules could solve the ureter mapping problem by providing real-time anatomic and functional imaging, even through intact peritoneum. Here we present the first-in-human experience of this chemical class, as well as the efficacy study in patients undergoing laparoscopic abdominopelvic surgery. The zwitterionic near-infrared fluorophore ZW800-1 is safe, has pharmacokinetic properties consistent with an ideal blood pool agent, and rapid elimination into urine after a single low-dose intravenous injection. Visualization of structure and function of the ureters starts within minutes after ZW800-1 injection and lasts several hours. Zwitterionic near-infrared fluorophores add value during laparoscopic abdominopelvic surgeries and could potentially decrease iatrogenic urethral injury. Moreover, ZW800-1 is engineered for one-step covalent conjugatability, creating possibilities for developing novel targeted ligands. Iatrogenic injury of the ureters is a feared complication of laparoscopic abdominal surgery. Here the authors present the NIR fluorophore ZW800-1 as an intraoperative imaging agent for ureter mapping, showing its safety, pharmacokinetic properties, and efficacy in healthy volunteers and patients undergoing abdominopelvic surgery.

Nitric oxide (NO) has important functions in biology and atmospheric chemistry as a toxin, signaling molecule, ozone depleting agent and the precursor of the greenhouse gas nitrous oxide (N 2 O). Although NO is a potent oxidant, and was available on Earth earlier than oxygen, it is unclear whether NO can be used by microorganisms for growth. Anaerobic ammonium-oxidizing (anammox) bacteria couple nitrite reduction to ammonium oxidation with NO and hydrazine as intermediates, and produce N 2 and nitrate. Here, we show that the anammox bacterium Kuenenia stuttgartiensis is able to grow in the absence of nitrite by coupling ammonium oxidation to NO reduction, and produce only N 2 . Under these growth conditions, the transcription of proteins necessary for NO generation is downregulated. Our work has potential implications in the control of N 2 O and NO emissions from natural and manmade ecosystems, where anammox bacteria contribute significantly to N 2 release to the atmosphere. We hypothesize that microbial NO-dependent ammonium oxidation may have existed on early Earth. Anammox bacteria couple nitrite reduction to ammonium oxidation, with nitric oxide (NO) and hydrazine as intermediates, and produce N 2 and nitrate. Here, Hu et al. show that an anammox bacterium can grow in the absence of nitrite by coupling ammonium oxidation to NO reduction, producing only N 2 .

BackgroundQuaternary ammonium compounds (QACs), commonly used in cleaning, disinfecting, and personal care products, have recently gained worldwide attention due to the massive use of disinfectants during the COVID-19 pandemic. However, despite extensive use of these chemicals, no studies have focused on the analysis of QACs in human milk, a major route of exposure for infants.ObjectiveOur objectives were to identify and measure QACs in breast milk and evaluate early-life exposure to this group of compounds for nursing infants.MethodsEighteen QACs, including 6 benzylalkyldimethyl ammonium compounds (BACs, with alkyl chain lengths of C8-C18), 6 dialkyldimethyl ammonium compounds (DDACs, C8-C18), and 6 alkyltrimethyl ammonium compounds (ATMACs, C8-C18), were measured in breast milk samples collected from U.S. mothers. Daily lactational intake was estimated based on the determined concentrations for 0–12 month old nursing infants.ResultsThirteen of the 18 QACs were detected in breast milk and 7 of them were found in more than half of the samples. The total QAC concentrations (ΣQAC) ranged from 0.33 to 7.4 ng/mL (median 1.5 ng/mL). The most abundant QAC was C14-BAC with a median concentration of 0.45 ng/mL. The highest median ΣQAC estimated daily intake (EDI) was determined for <1-month old infants based on the average (using the median concentration) and high (using the 95th percentile concentration) exposure scenarios (230 and 750 ng/kg body weight/day, respectively).SignificanceOur findings provide the first evidence of the detection of several QACs in breast milk and identify breastfeeding as an exposure pathway to QACs for nursing infants.Impact statementOur findings provide the first evidence of QAC occurrence in breast milk and identify breastfeeding as one of the exposure pathways to QACs for nursing infants.

Background Silver diamine fluoride (SDF) is a simple and non-invasive agent used to arrest early childhood caries (ECC). This study aimed to investigate potential changes to the oral microbiome in children with ECC who were treated with SDF and sodium fluoride (NaF) varnish at three different frequency regimens. Methods Forty-five children ( n  = 15 per group) with ECC were recruited from community-based dental clinics in Winnipeg, Canada into an open-label, parallel-group, randomized clinical trial testing three different treatment frequency regimens of SDF. A total of 195 carious lesions were treated with two applications of 38% SDF and 5% NaF varnish (and assessed over three study visits one month, four months, or six months apart. Dental plaque samples were collected at each visit. Sequencing of the V4-16 S rRNA and ITS1 rRNA genes were used to study the supragingival plaque microbiome. Results Microbial diversity analyses showed no significant differences in the overall microbiome after SDF treatment. However, significant changes in the abundance of specific bacteria and fungi, particularly Lactobacillus spp., Bifidobacterium spp., and Candida spp., were observed after treatment. Furthermore, overabundance of Streptococcus mutans and Candida dubliniensis at baseline was observed in children who had at least one caries lesion not arrested after one SDF application, compared to those who had 100% arrest rates. The overall arrest rates for treated carious lesions were 75.9% at the second visit and 92.8% at the third visit. Arrest rates were higher for all lesions after two applications of SDF with NaF varnish, and applications one month and four months apart had higher arrest rates (95.9% and 98.5%) than six months (81.1%) apart. Conclusions Applications of SDF with NaF varnish were an effective modality for arresting ECC, with higher arrest rates after two SDF applications. No loss of diversity but changes in the abundance of specific bacteria and fungi were observed after SDF treatment. Trial registration ClinicalTrials.gove NCT04054635 (first registered 13/08/2019).

The aim of the study was to examine the mean mineral density (MD) change in early proximal enamel caries lesions after applying silver diamine fluoride (SDF) using digital subtraction radiographic analysis at 6 and 12 months. A split-mouth, triple-blind, randomized controlled trial was conducted with thirty healthy participants aged 13–30 years old. Two active non-cavitated proximal caries lesions in different quadrants of each participant were randomly sampled and allocated to a test (38% SDF) and a control group (deionized water). Digital radiographs at baseline, 6 and 12 months were taken, and digital subtraction radiographic analysis was performed. The SDF group demonstrated a significantly higher mean MD on subtraction radiographs compared with the control group, after adjusting for baseline lesion depth and time, and for clustering within participants over time. The adjusted mean difference was 1.0 [95% CI 0.2, 1.9]. Therefore, applying SDF at baseline and 6 months resulted in significant remineralization compared with the control group over the 12-month period. These findings suggested that applying SDF can serve as an effective alternative treatment option for remineralizing early caries lesions on proximal surfaces.

INTRODUCTION:Opioids used to manage severe pain in acute pancreatitis (AP) might exacerbate the disease through effects on gastrointestinal and immune functions. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, may counteract these effects without changing analgesia.METHODS:This double-blind, randomized, placebo-controlled trial included adult patients with AP and systemic inflammatory response syndrome at 4 Danish centers. Patients were randomized to receive 5 days of continuous intravenous methylnaltrexone (0.15 mg/kg/d) or placebo added to the standard of care. The primary end point was the Pancreatitis Activity Scoring System score after 48 hours of treatment. Main secondary outcomes included pain scores, opioid use, disease severity, and mortality.RESULTS:In total, 105 patients (54% men) were randomized to methylnaltrexone (n = 51) or placebo (n = 54). After 48 hours, the Pancreatitis Activity Scoring System score was 134.3 points in the methylnaltrexone group and 130.5 points in the placebo group (difference 3.8, 95% confidence interval [CI] −40.1 to 47.6; P = 0.87). At 48 hours, we found no differences between the groups in pain severity (0.0, 95% CI −0.8 to 0.9; P = 0.94), pain interference (−0.3, 95% CI −1.4 to 0.8; P = 0.55), and morphine equivalent doses (6.5 mg, 95% CI −2.1 to 15.2; P = 0.14). Methylnaltrexone also did not affect the risk of severe disease (8%, 95% CI −11 to 28; P = 0.38) and mortality (6%, 95% CI −1 to 12; P = 0.11). The medication was well tolerated.DISCUSSION:Methylnaltrexone treatment did not achieve superiority over placebo for reducing the severity of AP.

The emergence of antibiotic resistance genes (ARGs) in microbes can be largely attributed to the abuse and misuse of antibiotics and biocides. Quaternary ammonium compounds (QACs) have been used worldwide as common disinfectants and detergents; however, their potential impact on the spread and diffusion of ARGs is still unknown. In this study, we detected the QAC resistance gene ( qacEΔ1 ), the 1 integron gene ( intI1 ), and 12 ARGs ( sul1 , sul2 , cfr , cml , fexA , tetA , tetG , tetQ , tetX , ermB , bla TEM , and dfrA1 ) in 48 water samples from three watersheds by quantitative PCR (qPCR). We investigated the evolution of bacterial antibiotic resistance under QAC and antibiotic environmental pressures by long-term continuous culture. In addition, five QACs were selected to investigate the effect of QAC on the efficiency of conjugation transfer. The changes in bacterial cell membrane and production of reactive oxygen species (ROS) were detected by flow cytometry, revealing the mechanism by which QAC affects the spread of antibiotic resistance. Our results showed that the QAC resistance gene was ubiquitous in watersheds and it had significant correlation with intI1 and seven ARGs ( r  = 0.999, p  < 0.01). QACs could increase the resistance of bacteria to multiple antibiotics. Furthermore, all five QACs promoted the conjugation transfer of the RP4 plasmid; the optimal concentration of QACs was about 10 −1 –10 −2  mg/L and their transfer efficiencies were between 1.33 × 10 −6 and 8.87 × 10 −5 . QACs enhanced membrane permeability of bacterial cells and stimulated bacteria to produce ROS, which potentially promoted the transfer of plasmids between bacteria. In conclusion, this study demonstrated that QACs may facilitate the evolution and gene transfer of antibiotic resistance gene among microbiome.

This study investigated the safety and efficacy of subcutaneous methylnaltrexone, a μ-opioid–receptor antagonist, for treating opioid-induced constipation in patients with advanced illness. Methylnaltrexone rapidly induced laxation without affecting central analgesia or precipitating withdrawal. This study investigated the safety and efficacy of subcutaneous methylnaltrexone for treating opioid-induced constipation in patients with advanced illness. Methylnaltrexone rapidly induced laxation without affecting central analgesia or precipitating withdrawal. Clinicians often use opioids to treat moderate-to-severe pain; however, opioids frequently induce or aggravate constipation. Empirically, laxative therapy may be burdensome and ineffective and result in temporally unpredictable responses. In addition, severe opioid-induced constipation may limit opioid therapy, worsening analgesia. These drawbacks can substantially compromise the quality of life, especially in patients with advanced illness. Opioid-induced constipation is predominantly mediated by gastrointestinal μ-opioid receptors. 1 , 2 Selective blockade of these peripheral receptors might relieve constipation without compromising centrally mediated effects of opioid analgesia or precipitating withdrawal. N-methylation of the uncharged systemic opioid antagonist, naltrexone, 3 results in a charged derivative, methylnaltrexone, which . . .

Patients admitted to hospital can acquire multidrug-resistant organisms and Clostridium difficile from inadequately disinfected environmental surfaces. We determined the effect of three enhanced strategies for terminal room disinfection (disinfection of a room between occupying patients) on acquisition and infection due to meticillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, C difficile, and multidrug-resistant Acinetobacter. We did a pragmatic, cluster-randomised, crossover trial at nine hospitals in the southeastern USA. Rooms from which a patient with infection or colonisation with a target organism was discharged were terminally disinfected with one of four strategies: reference (quaternary ammonium disinfectant except for C difficile, for which bleach was used); UV (quaternary ammonium disinfectant and disinfecting ultraviolet [UV-C] light except for C difficile, for which bleach and UV-C were used); bleach; and bleach and UV-C. The next patient admitted to the targeted room was considered exposed. Every strategy was used at each hospital in four consecutive 7-month periods. We randomly assigned the sequence of strategies for each hospital (1:1:1:1). The primary outcomes were the incidence of infection or colonisation with all target organisms among exposed patients and the incidence of C difficile infection among exposed patients in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01579370. 31 226 patients were exposed; 21 395 (69%) met all inclusion criteria, including 4916 in the reference group, 5178 in the UV group, 5438 in the bleach group, and 5863 in the bleach and UV group. 115 patients had the primary outcome during 22 426 exposure days in the reference group (51·3 per 10 000 exposure days). The incidence of target organisms among exposed patients was significantly lower after adding UV to standard cleaning strategies (n=76; 33·9 cases per 10 000 exposure days; relative risk [RR] 0·70, 95% CI 0·50–0·98; p=0·036). The primary outcome was not statistically lower with bleach (n=101; 41·6 cases per 10 000 exposure days; RR 0·85, 95% CI 0·69–1·04; p=0·116), or bleach and UV (n=131; 45·6 cases per 10 000 exposure days; RR 0·91, 95% CI 0·76–1·09; p=0·303) among exposed patients. Similarly, the incidence of C difficile infection among exposed patients was not changed after adding UV to cleaning with bleach (n=38 vs 36; 30·4 cases vs 31·6 cases per 10 000 exposure days; RR 1·0, 95% CI 0·57–1·75; p=0·997). A contaminated health-care environment is an important source for acquisition of pathogens; enhanced terminal room disinfection decreases this risk. US Centers for Disease Control and Prevention.

BackgroundPlants can utilize two major forms of inorganic N: NO3− (nitrate) and NH4+ (ammonium). In some cases, the preference of one form over another (denoted as β) can appear to be quite pronounced for a plant species, and can be an important determinant and predictor of its distribution and interactions with other species. In many other cases, however, assignment of preference is not so straightforward and must take into account a wide array of complex physiological and environmental features, which interact in ways that are still not well understood.ScopeThis Viewpoint presents a discussion of the key, and often co-occurring, factors that join to produce the complex phenotypic composite referred to by the deceptively simple term ‘N-source preference’.ConclusionsN-source preference is much more complex a biological phenomenon than is often assumed, and general models predicting how it will influence ecological processes will need to be much more sophisticated than those that have been so far developed.