Notes

The effects of different numbers of head-of-bed level around the respiratory system design and also water flow pursuing thyroidectomy: a new randomized managed trial.
To assess the efficacy and safety of dual antiangiogenesis agents, bevacizumab plus trebananib, without chemotherapy, in first-line treatment of metastatic colorectal cancer (mCRC).

This open-label phase II study enrolled patients with unresectable mCRC with no prior systemic treatment. All patients received bevacizumab 7.5 mg/kg 3-weekly and trebananib 15 mg/kg weekly. The primary endpoint was disease control [stable disease, partial response (PR), or complete response (CR)] at 6 months (DC6m). Secondary endpoints included toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarkers in plasma angiogenesis-related proteins, tumor gene expression, and plasma antibodies to tumor antigens were examined.

Forty-five patients were enrolled from four Australian sites. DC6m was 63% [95% confidence interval (CI), 47-77]. ORR was 17% (95% CI, 7-32), comprising of seven PRs. Median duration of response was 20 months (range, 10-48 months). Median PFS was ploratory biomarker results raise the hypothesis that the antiangiogenic combination may enable the antitumor immune response in immunotolerant colorectal cancer.
Detection of leptomeningeal metastasis is hampered by limited sensitivities of currently used techniques MRI and cytology of cerebrospinal fluid (CSF). Detection of cell-free tumor DNA in CSF has been proposed as a tumor-specific candidate to detect leptomeningeal metastasis at an earlier stage. The aim of this study was to investigate mutation and aneuploidy status in CSF-derived cell-free DNA (cfDNA) of patients with breast cancer with a clinical suspicion of leptomeningeal metastasis.

cfDNA was isolated from stored remnant CSF and analyzed by targeted next-generation sequencing (NGS;
= 30) and the modified fast aneuploidy screening test-sequencing system (mFAST-SeqS;
= 121). The latter method employs selective amplification of long interspaced nuclear elements sequences that are present throughout the genome and allow for fast and cheap detection of aneuploidy. We compared these results with the gold standard to diagnose leptomeningeal metastasis cytology.

Leptomeningeal metastasis was cytology proven in 13 of 121 patients. Low DNA yields resulted in insufficient molecular coverage of NGS for the majority of samples (success rate, 8/30). The mFAST-SeqS method, successful in 112 of 121 (93%) samples, detected genome-wide aneuploidy in 24 patients. Ten of these patients had cytology-proven leptomeningeal metastasis; 8 additional patients were either concurrently diagnosed with central nervous system metastases by radiological means or developed these soon after the lumbar puncture. The remaining six cases were suspected of leptomeningeal metastasis, but could not be confirmed by cytology or imaging. Aneuploidy was associated with development of leptomeningeal metastasis and significantly worse overall survival.

Aneuploidy in CSF-derived cfDNA may provide a promising biomarker to improve timely detection of leptomeningeal metastasis.
Aneuploidy in CSF-derived cfDNA may provide a promising biomarker to improve timely detection of leptomeningeal metastasis.
T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor.

This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis.

No dose-limiting toxicities were observed in the monotherapy (
= 30) or combination (
= 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (obsynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
Non-contrast CT aortic valve calcium scoring ignores the contribution of valvular fibrosis in aortic stenosis. We assessed aortic valve calcific and non-calcific disease using contrast-enhanced CT.

This was a post hoc analysis of 164 patients (median age 71 (IQR 66-77) years, 78% male) with aortic stenosis (41 mild, 89 moderate, 34 severe; 7% bicuspid) who underwent echocardiography and contrast-enhanced CT as part of imaging studies. Calcific and non-calcific (fibrosis) valve tissue volumes were quantified and indexed to annulus area, using Hounsfield unit thresholds calibrated against blood pool radiodensity. The fibrocalcific ratio assessed the relative contributions of valve fibrosis and calcification. The fibrocalcific volume (sum of indexed non-calcific and calcific volumes) was compared with aortic valve peak velocity and, in a subgroup, histology and valve weight.

Contrast-enhanced CT calcium volumes correlated with CT calcium score (r=0.80, p<0.001) and peak aortic jet velocity (r=0.55, p&ltvalve obstruction.Pigs are major reservoirs of resistant Enterobacteriaceae that can reach humans through consumption of contaminated meat or vegetables grown in manure-fertilized soil. Samples were collected from sows during lactation and their piglets at five time points spanning the production cycle. Cefotaxime-resistant bacteria were quantified and isolated from feed, feces, manures and carcasses of pigs reared with penicillin-using or antibiotic-free husbandries. The isolates were characterized by antibiotic susceptibility testing, whole genome sequencing and conjugation assays. The extended spectrum β-lactamase (ESBL) phenotype was more frequent in isolates originating from antibiotic-free animals, while the bacteria isolated from penicillin-using animals were on average resistant to a greater number of antibiotics. The ESBL-encoding genes identified were blaCTX-M-1, blaCTX-M-15 and blaCMY-2 and they co-localised on plasmids with various genes encoding resistance to ß-lactams, co-trimoxazole, phenicols and tetracycline, of antimicrobials are used in agriculture to ensure animal welfare and productivity, and are arguably a driving force for the persistence of environmental and food-borne resistant bacteria. This study evaluated the impact of conventional, organic and other antibiotic-free husbandry practices on the frequency and nature of antimicrobial resistance genes and multidrug resistant enterobacteria. It provides knowledge about the relative contribution of specific resistance determinants to observed antibiotic resistance. It also showed the clear co-selection of genes coding for extended-spectrum beta-lactamases and genes coding for the resistance to antibiotics commonly used for prophylaxis or in curative treatments in pig operations.Soil organic carbon (SOC) plays an important role in regulating global climate change, carbon and nutrient cycling in soils, and soil moisture. Organic matter (OM) additions to soils can affect the rate at which SOC is mineralized by microbes, with potentially important effects on SOC stocks. Understanding how pyrogenic organic matter (PyOM) affects the cycling of native SOC (nSOC) and the soil microbes responsible for these effects is important for fire-affected ecosystems as well as for biochar-amended systems. We used an incubation trial with five different soils from National Ecological Observatory Network sites across the US and 13C-labelled 350°C corn stover PyOM and fresh corn stover OM to trace nSOC-derived CO2 emissions with and without PyOM and OM amendments. We used high-throughput sequencing of rRNA genes to characterize bacterial, archaeal, and fungal communities and their response to PyOM and OM in soils that were previously stored at -80°C. We found that the effects of amendments on nSOC-derivec matter (PyOM)) affects existing SOM stocks has become increasingly important, both due to changing fire regimes, and to interest in "biochar" - pyrogenic organic matter that is produced intentionally for carbon management or as an agricultural soil amendment. We found that soils with less SOM were more prone to increased losses with PyOM (and fresh organic matter) additions, and that soil microbial communities changed more in soils that also had greater SOM losses with PyOM additions. This suggests that soils that already have low SOM content may be particularly vulnerable to short-term increases in SOM loss, and that a subset of the soil microbial community is likely responsible for these effects.The composition of tick microbiomes varies both within and among tick species. Whether this variation is intrinsic (related to tick characteristics) or extrinsic (related to vertebrate host and habitat) is poorly understood but important, as microbiota can influence the reproductive success and vector competence of ticks. We aimed to uncover what intrinsic and extrinsic factors best explain the microbial composition and taxon richness of 11 species of neotropical ticks collected from eight species of small mammals in 18 forest fragments across central Panama. Microbial richness varied among tick species, life stages, and collection sites but was not related to host blood source. Microbiome composition was best explained by tick life stage, with bacterial assemblages of larvae being a subset of those of nymphs. Collection site explained most of the bacterial taxa with differential abundance across intrinsic and extrinsic factors. Francisella and Rickettsia were highly prevalent, but their proportional abundancck microbial composition as well as which specific microbes contribute to differences across tick species, tick life stages, the mammals they fed on, and the locations from where they were sampled. Furthermore, this study provides revelations of how notable tick-associated bacterial genera are interacting with other tick-associated microbes as well as the forest animals they encounter.Shewanella oneidensis is a model strain of the electrochemical active bacteria (EAB) because of its strong capability of extracellular electron transfer (EET) and genetic tractability. In this study, we investigated the effect of carbon sources on EET in S. oneidensis by using reduction of palladium ions (Pd(II)) as a model and found that pyruvate greatly accelerated the Pd(II) reduction compared with lactate by resting cells. Both Mtr pathway and hydrogenases played a role in Pd(II) reduction when pyruvate was used as a carbon source. Furthermore, in comparison with lactate-feeding S. oneidensis, the transcriptional levels of formate dehydrogenases involving in pyruvate catabolism, Mtr pathway, and hydrogenases in pyruvate-feeding S. oneidensis were up-regulated. Mechanistically, the enhancement of electron generation from pyruvate catabolism and electron transfer to Pd(II) explains the pyruvate effect on Pd(II) reduction. Interestingly, a 2-h time window is required for pyruvate to regulate transcription of these genes and profoundly improve Pd(II) reduction capability, suggesting a hierarchical regulation for pyruvate sensing and response in S. oneidensisIMPORTANCE The unique respiration of EET is crucial for the biogeochemical cycling of metal elements and diverse applications of EAB. Although a carbon source is a determinant factor of bacterial metabolism, the research into the regulation of carbon source on EET is rare. In this work, we reported the pyruvate-specific regulation and improvement of EET in S. oneidensis and revealed the underlying mechanism, which suggests potential targets to engineer and improve the EET efficiency of this bacterium. This study sheds light on the regulatory role of carbon sources in anaerobic respiration in EAB, providing a way to regulate EET for diverse applications from a novel perspective.Agrobacterium tumefaciens S33 degrades nicotine through a hybrid of the pyridine and pyrrolidine pathways. The oxidation of 6-hydroxypseudooxynicotine to 6-hydroxy-3-succinoyl-semialdehyde-pyridine by 6-hydroxypseudooxynicotine dehydrogenase (Pno) is an important step in the breakdown of the N-heterocycle in this pathway. Although Pno has been characterized, the reaction is not fully understood; what is known is that it starts at a high speed followed by a rapid drop in the reaction rate, leading to the formation of a very small amount of product. In this study, we speculated that an unstable imine intermediate that is toxic with regard to the metabolism is produced in the reaction. We found that a Rid protein (designated Rid-NC) encoded by a gene in the nicotine-degrading gene cluster enhanced the reaction. Rid is a widely distributed family of small proteins with various functions, and some subfamilies have deaminase activity to eliminate the toxicity of the reactive intermediate, imine. Biochemical analysene degradation by Agrobacterium tumefaciens S33. Rid-NC hydrolyzed the presumed reactive imine intermediate produced in the reaction to remove its toxicity on Pno. The finding furthers our understanding of the metabolic process of the toxic N-heterocyclic aromatic compounds in microorganisms. This study demonstrated that the Rid family of proteins also functions in the metabolism of N-heterocyclic aromatic alkaloids, in addition to the amino acid metabolism, and that Rid6-subfamily proteins also have deaminase activity, similar to the RidA subfamily. The ability of reactive imines to damage a non-pyridoxal-5'-phosphate-dependent enzyme was reported. This study provides new insights into the function of the Rid family of proteins.Biobutanol is a valuable biochemical and one of the most promising biofuels. Clostridium saccharoperbutylacetonicum N1-4 is a hyperbutanol-producing strain. However, its strong autolytic behavior leads to poor cell stability, especially during continuous fermentation, thus limiting the applicability of the strain for long-term and industrial-scale processes. In this study, we aimed to evaluate the role of autolysin genes within the C. saccharoperbutylacetonicum genome related to cell autolysis and further develop more stable strains for enhanced butanol production. First, putative autolysin-encoding genes were identified in the strain based on comparison of amino acid sequence with homologous genes in other strains. Then, by overexpressing all these putative autolysin genes individually and characterizing the corresponding recombinant strains, four key genes were pinpointed to be responsible for significant cell autolysis activities. Further, these key genes were deleted using CRISPR-Cas9. Fermentation characterization demonstrated enhanced performance of the resultant mutants. Results from this study reveal valuable insights concerning the role of autolysins for cell stability and solvent production, and they provide an essential reference for developing robust strains for enhanced biofuel and biochemical production.IMPORTANCE Severe autolytic behavior is a common issue in Clostridium and many other microorganisms. This study revealed the key genes responsible for the cell autolysis within Clostridium saccharoperbutylacetonicum, a prominent platform for biosolvent production from lignocellulosic materials. The knowledge generated in this study provides insights concerning cell autolysis in relevant microbial systems and gives essential references for enhancing strain stability through rational genome engineering.Homologous recombination (HR)-deficient cancers are sensitive to poly-ADP ribose polymerase inhibitors (PARPi), which have shown clinical efficacy in the treatment of high-grade serous cancers (HGSC). However, the majority of patients will relapse, and acquired PARPi resistance is emerging as a pressing clinical problem. Here we generated seven single-cell clones with acquired PARPi resistance derived from a PARPi-sensitive TP53-/- and BRCA1-/- epithelial cell line generated using CRISPR/Cas9. These clones showed diverse resistance mechanisms, and some clones presented with multiple mechanisms of resistance at the same time. Genomic analysis of the clones revealed unique transcriptional and mutational profiles and increased genomic instability in comparison with a PARPi-sensitive cell line. Clonal evolutionary analyses suggested that acquired PARPi resistance arose via clonal selection from an intrinsically unstable and heterogenous cell population in the sensitive cell line, which contained preexisting drug-tolerant cells. Similarly, clonal and spatial heterogeneity in tumor biopsies from a clinical patient with BRCA1-mutant HGSC with acquired PARPi resistance was observed. In an imaging-based drug screening, the clones showed heterogenous responses to targeted therapeutic agents, indicating that not all PARPi-resistant clones can be targeted with just one therapy. Furthermore, PARPi-resistant clones showed mechanism-dependent vulnerabilities to the selected agents, demonstrating that a deeper understanding on the mechanisms of resistance could lead to improved targeting and biomarkers for HGSC with acquired PARPi resistance. SIGNIFICANCE This study shows that BRCA1-deficient cells can give rise to multiple genomically and functionally heterogenous PARPi-resistant clones, which are associated with various vulnerabilities that can be targeted in a mechanism-specific manner.Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor α (ERα) negativity. Here we explored the role of the second ER subtype, ERβ, and report expression in IBC tumors and its correlation with reduced metastasis. Ablation of ERβ in IBC cells promoted cell migration and activated gene networks that control actin reorganization, including G-protein-coupled receptors and downstream effectors that activate Rho GTPases. Analysis of preclinical mouse models of IBC revealed decreased metastasis of IBC tumors when ERβ was expressed or activated by chemical agonists. Our findings support a tumor-suppressive role of ERβ by demonstrating the ability of the receptor to inhibit dissemination of IBC cells and prevent metastasis. On the basis of these findings, we propose ERβ as a potentially novel biomarker and therapeutic target that can inhibit IBC metastasis and reduce its associated mortality. SIGNIFICANCE These findings demonstrate the capacity of ERβ to elicit antimetastatic effects in highly aggressive inflammatory breast cancer and propose ERβ and the identified associated genes as potential therapeutic targets in this disease.Circadian disruption may play a role in carcinogenesis. Recent research suggests that light at night (LAN), a circadian disruptor, may be a risk factor for cancer. Moreover, LAN has been linked to obesity and diabetes, two risk factors for pancreatic ductal adenocarcinoma (PDAC). Here we examine the relationship between LAN and PDAC in an epidemiologic study of 464,371 participants from the NIH-AARP Diet and Health Study. LAN was estimated from satellite imagery at baseline (1996), and incident primary PDAC cases were ascertained from state cancer registries. Cox proportional hazards models were used to estimate HRs and two-sided 95% confidence intervals (CI) for the association between quintiles of LAN and PDAC in the overall population stratified by sex. Over up to 16.2 years of follow-up, a total of 2,502 incident PDAC were identified in the cohort. Higher estimated LAN exposure was associated with an elevated PDAC risk. Compared with those living in areas in the lowest LAN quintile, those in areas in the highest quintile had a 27% increase PDAC risk [HR (95% CI), 1.24 (1.03-1.49)], with similar risk for men [1.21 (0.96-1.53)] and women [1.28 (0.94-1.75)]. In addition, stronger associations were observed in normal and overweight groups compared with the obese group (Pinteraction = 0.03). Our results support the hypothesis that LAN and circadian disruption may be risk factors for PDAC. SIGNIFICANCE Our study suggests that higher LAN is a risk factor for pancreatic cancer, contributing to the growing literature that demonstrates the potentially adverse health effects of light pollution.The dysregulated sepsis-induced cytokine storm evoked during systemic infection consists of biphasic and interconnected pro- and anti-inflammatory responses. The contrasting inflammatory cytokine responses determine the severity of the septic event, lymphopenia, host survival, and the ensuing long-lasting immunoparalysis state. NK cells, because of their capacity to elaborate pro- (i.e., IFN-γ) and anti-inflammatory (i.e., IL-10) responses, exist at the inflection of sepsis-induced inflammatory responses. Thus, NK cell activity could be beneficial or detrimental during sepsis. In this study, we demonstrate that murine NK cells promote host survival during sepsis by limiting the scope and duration of the cytokine storm. Specifically, NK cell-derived IL-10, produced in response to IL-15, is relevant to clinical manifestations in septic patients and critical for survival during sepsis. This role of NK cells demonstrates that regulatory mechanisms of classical inflammatory cells are beneficial and critical for controlling systemic inflammation, a notion relevant for therapeutic interventions during dysregulated infection-induced inflammatory responses.Acute infection is implicated as a trigger for chronic inflammatory disease, but the full basis for this switch is uncertain. In this study, we examine this issue using a mouse model of chronic lung disease that develops after respiratory infection with a natural pathogen (Sendai virus). We investigate this model using a combination of TLR3-deficient mice and adoptive transfer of immune cells into these mice versus the comparable responses in wild-type mice. We found that acute and transient expression of TLR3 on monocyte-derived dendritic cells (moDCs) was selectively required to induce long-term expression of IL-33 and consequent type 2 immune-driven lung disease. Unexpectedly, moDC participation was not based on canonical TLR3 signaling and relied instead on a trophic effect to expand the alveolar epithelial type 2 cell population beyond repair of tissue injury and thereby provide an enriched and persistent cell source of IL-33 required for progression to a disease phenotype that includes lung inflammation, hyperreactivity, excess mucus production, and remodeling. The findings thereby provide a framework wherein viral infection activates TLR3 in moDCs as a front-line immune cell niche upstream of lung epithelial cells to drive the type 2 immune response, leading to chronic inflammatory diseases of the lung (such as asthma and chronic obstructive pulmonary disease in humans) and perhaps progressive and long-term postviral disease in general.Our studies have previously shown a role for persistent TSLP production in the lungs of mice after early-life respiratory syncytial virus (RSV) infection that leads to an altered immune phenotype, including accumulation of "inflammatory" dendritic cells (DC). This study investigates the role of TSLP driving systemic trained immunity in DC in early-life RSV-infected mice. Bone marrow-derived DCs (BMDC) from early-life RSV-infected mice at 4 wk postinfection showed enhanced expression of costimulatory molecules and cytokines, including Tslp, that regulate immune cell function. The adoptive transfer of BMDC grown from early-life RSV-infected mice was sufficient to exacerbate allergic disease development. The addition of recombinant TSLP during differentiation of BMDC from naive mice induced a similar altered phenotype as BMDC grown from early-life RSV-infected mice, suggesting a role for TSLP in the phenotypic changes. To assess the role of TSLP in these changes, global transcriptomic characterization of TSLPR-/- BMDC infected with RSV was performed and showed a higher upregulation of type 1 IFN genes and concomitant downregulation of inflammatory genes. Assay for transposase-accessible chromatin using sequencing analysis demonstrated that TSLPR-/- BMDC had a parallel gain in physical chromatin accessibility near type 1 genes and loss in accessibility near genes related to RSV pathology, with IFN regulatory factor 4 (IRF4) and STAT3 predicted as top transcription factors binding within differentially accessible regions in wild-type. Importantly, these studies show that in the absence of TSLP signaling, BMDC are able to mount an appropriate type 1 IFN-associated antiviral response to RSV. In summary, RSV-induced TSLP alters chromatin structure in DC to drive trained innate immunity and activates pathogenic gene programs in mice.Tumor-infiltrating myeloid-derived suppressor cells (MDSC) are associated with poor survival outcomes in many human cancers. MDSCs inhibit T cell-mediated tumor immunity in part because they strongly inhibit T-cell function. However, whether MDSCs inhibit early or later steps of T-cell activation is not well established. Here we show that MDSCs inhibited proliferation and induced apoptosis of CD8+ T cells even in the presence of dendritic cells (DC) presenting a high-affinity cognate peptide. This inhibitory effect was also observed with delayed addition of MDSCs to cocultures, consistent with functional data showing that T cells expressed multiple early activation markers even in the presence of MDSCs. Single-cell RNA-sequencing analysis of CD8+ T cells demonstrated a p53 transcriptional signature in CD8+ T cells cocultured with MDSCs and DCs. Confocal microscopy showed induction of DNA damage and nuclear accumulation of activated p53 protein in a substantial fraction of these T cells. DNA damage in T cells was dependent on the iNOS enzyme and subsequent nitric oxide release by MDSCs. Small molecule-mediated inhibition of iNOS or inactivation of the Nos2 gene in MDSCs markedly diminished DNA damage in CD8+ T cells. DNA damage in CD8+ T cells was also observed in KPC pancreatic tumors but was reduced in tumors implanted into Nos2-deficient mice compared with wild-type mice. These data demonstrate that MDSCs do not block early steps of T-cell activation but rather induce DNA damage and p53 pathway activation in CD8+ T cells through an iNOS-dependent pathway.
To evaluate the association between human papillomavirus (HPV) vaccination and serious adverse events in adolescent girls in South Korea.

Cohort study.

A large linked database created by linking the Korea Immunization Registry Information System and the National Health Information Database, between January 2017 and December 2019.

441 399 girls aged 11-14 years who had been vaccinated in 2017 382 020 had been vaccinated against HPV and 59 379 had not been vaccinated against HPV.

Outcomes were 33 serious adverse events, including endocrine, gastrointestinal, cardiovascular, musculoskeletal, haematological, dermatological, and neurological diseases. A cohort design was used for the primary analysis and a self-controlled risk interval design for the secondary analysis; both analyses used a risk period of one year after HPV vaccination for each outcome. Incidence rate and adjusted rate ratios were estimated using Poisson regression in the primary analysis, comparing the HPV vaccinated group with the HPV ying follow-up periods and for vaccine subtypes.

In this nationwide cohort study, with more than 500 000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events using both cohort analysis and self-controlled risk interval analysis. Inconsistent findings for migraine should be interpreted with caution considering its pathophysiology and the population of interest.
In this nationwide cohort study, with more than 500 000 doses of HPV vaccines, no evidence was found to support an association between HPV vaccination and serious adverse events using both cohort analysis and self-controlled risk interval analysis. Inconsistent findings for migraine should be interpreted with caution considering its pathophysiology and the population of interest.
Acute pain after surgery is one of the most frequent indications for opioid prescribing in children. Opioids are often not stored or disposed of safely after their use, placing children and others in the home at risk for accidental ingestion or intentional misuse. We currently lack evidence-based guidelines for post-operative pain management after common ambulatory pediatric urologic procedures. Thus, each surgeon must decide if and how much opioid to prescribe based on his/her own assumptions of perceived post-operative pain.

As part of an effort to establish opioid prescribing guidelines across two academic centers, the objectives of this study were to evaluate current variability in pediatric urologists' opioid prescribing factors and identify patients at greatest risk of being prescribed high doses of opioids after common ambulatory pediatric urologic procedures.

We retrospectively evaluated post-operative opioid prescribing patterns after common ambulatory pediatric urology procedures (circumcisionioid, and those 0-2 years receiving the highest number of doses. This highlights the need for evidence-based guidelines for post-operative pain management after ambulatory pediatric urologic surgeries.Key insights A Addressing a complex problem like harassment in VA medical facilities requires committed, engaged collaboration at multiple levels of the organization. B Timely feedback of initial research findings to operations partners enabled rapid and more responsive development of new programs and policies. C Our research-clinical partnership has enabled us to pursue targeted change from the outset, while incorporating real-time findings from embedded researchers working to develop a comprehensive understanding of the problem.
The prescribing process for children with cancer is complex, and errors can occur at any step. As a result, many interventions have been used to reduce errors. However, few of them have been designed based on an understanding of the prescriber behaviour that can lead to errors. In order to design effective behaviour change interventions, it is important first to understand the prescribing process and identify prescriber behaviours that could be targeted for change.

To describe the prescribing process in a paediatric oncology ward and to identify prescriber behaviours during prescription writing that could be targeted to reduce errors.

This study employed two sequential phases. First, the prescribing process was observed and then described using the hierarchical task analysis (HTA) method. Second, prescriber tasks identified from the HTA were analysed using the behaviour change wheel (BCW) approach to identify promising behaviours for change. These identified behaviours were prioritised based on informatr work environments to achieve the desired change in these identified behaviours.Because of the high incidence of cytomegalovirus (CMV) seropositivity in the population, CMV infection is a common and severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Taiwan. Here we propose a CMV management strategy for patients undergoing allo-HSCT from the Taiwanese perspective, which focuses on the epidemiology, diagnosis, monitoring, prophylaxis, and treatment of CMV infection after allo-HSCT. In terms of CMV monitoring, weekly CMV monitoring with the COBAS® AmpliPrep system is the standard approach because the pp65 CMV antigenemia assay has a lower sensitivity than CMV monitoring with the COBAS® AmpliPrep system. However, pp65 CMV antigenemia assay has a better correlation with clinical symptoms in immunocompromised patients. A 14-week prophylactic course of letermovir is recommended for allo-HSCT recipients in Taiwan, especially for recipients of hematopoietic stem cells from mismatched unrelated and haploidentical donors. Preemptive ganciclovir therapy should be initiated when the CMV viral load exceeds 1000 copies/mL, and should not be discontinued until CMV DNA is no longer detected in the blood. For allo-HSCT recipients who have CMV-related diseases, ganciclovir with or without CMV-specific intravenous immunoglobulin is the standard of care. The limited availability of foscarnet, an alternative for patients who are not responsive to or cannot tolerate ganciclovir, is a crucial issue in Taiwan. For pediatric allo-HSCT recipients, more data are needed to propose a CMV management recommendation.A series of new 4-alkoxy/aryloxyphenyl cyclopropyl methane oxime derivatives 2(a-k) were synthesized and fully characterized by FT-IR, 1H-NMR, 13C-NMR and Mass spectrometry techniques. All the synthesized compounds 2(a-k) were assayed for in vitro antibacterial activity against a selected bacterial strain and the compound (2 h) and (2k) exerted excellent activity against Staphylococcus aureus, Escherichia coli and Salmonella typhi strains. The potency of inhibitors and possible interaction mechanism of synthetic oxime (2k) with 1GQN enzyme on Salmonella typhi was explored by molecular docking method. Amongst the all synthesized compounds, the quantum chemical calculations were done for Cyclopropyl(4-(pyridin-3-ylmethoxy)phenyl)methanone oxime (2k). The first hyperpolarizability calculation performed in different solvent such as CHCl3, CH2Cl2 and DMSO and compared to the reference compound urea. In addition, natural bond orbital analysis (NBO), local reactivity descriptors, thermodynamic properties, Mulliken charges, molecular electrostatic potential (MEP), frontier molecular orbitals (FMO) analysis were explored using theoretical calculations.
Data on the differential impact of chronic kidney disease (CKD) on the outcomes of endovascular stroke interventions (ESI) for acute ischemic stroke (AIS) are limited.

Adult patients who underwent ESI for AIS between October 1st, 2015 and September 30th, 2019, were identified in a national multicenter database. The primary endpoints were in-hospital mortality and poor functional outcomes. Secondary endpoints included intracranial hemorrhage, mechanical ventilation, pneumonia, myocardial infarction, blood transfusion, length of stay, and cost. A multilevel mixed-effects regression model was used to derive adjusted outcomes.

A total of 22,193 AIS patients who underwent ESI at 99 centers were included. Among those, 18,881 (85%) had no CKD, and 3312 (15%) had CKD. Patients with CKD were older and had a higher prevalence of key comorbidities. After multivariable risk adjustment, patients with CKD had significantly higher in-hospital mortality (Odds Ratio [OR] 1.55 [95% Confidence Interval] [CI] 1.40-1.73, p<0.01), and poor functional outcomes (OR 1.38, 95%CI 1.26-1.50, p<0.01). Major complications, including mechanical ventilation, pneumonia, blood transfusion, and myocardial infarction, were more common among CKD patients, who also had longer hospitalizations and accrued higher cost.

The presence of CKD in patients with AIS treated with ESI is an independent predictor of in-hospital mortality and poor functional outcomes at discharge.
The presence of CKD in patients with AIS treated with ESI is an independent predictor of in-hospital mortality and poor functional outcomes at discharge.
Guidelines recommend dual antiplatelet therapy (DAPT) after transcatheter aortic valve replacement (TAVR) but guidelines predate the publication of the largest randomized trial. There have been few trials in the field to date, and with a small number of total patients; pooling their results may therefore be helpful.

We systematically identified all randomized trials comparing SAPT to DAPT after TAVR. The primary endpoint was the risk of major bleeding. Secondary endpoints included all bleeding, life-threatening bleeding, stroke, myocardial infarction, death and cardiac death.

Four trials, randomizing 1086 participants, were eligible (541 randomized to SAPT and 545 randomized to DAPT). The weighted mean follow-up was 9.1months. The risk of major bleeding was significantly increased after DAPT (relative risk (RR) 2.36, 95% confidence interval (CI) 1.27 to 4.40, P=0.007). There was a similar increased risk for all bleeding (RR 1.65, 95% CI 1.24 to 2.19, P<0.001), although not for life-threatening bleedinger follow-up are required to assess for any potential differences in ischemic endpoints or mortality.
There is no consensus on the best treatment of undilatable coronary in-stent restenosis (ISR) regardless of the number of stent layers. We aimed to evaluate the procedural and clinical outcomes of rotational atherectomy (RA) to treat undilatable coronary ISR with single or multiple stent layers.

We retrospectively evaluated consecutive patients treated with RA for undilatable ISR with single or multiple stent layers in the Mount Sinai catheterization laboratory between January 2016 and September 2018. Procedural success was defined as angiographic success without in-hospital major adverse cardiac events (MACE) a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR). Clinical outcomes were assessed at one-year post-procedure.

A total of 26 patients were included in the study, in which 18 (69.2%) patients were with multiple stent layers. After RA, 9 (34.6%) were received a new drug-eluting stent, and 6 (23.1%) were treated with intravascular brachytherapy. Angiographic success was achieved in 24 (92.3%) patients, and procedural success was achieved in 22 (84.6%) patients. In-hospital MACE occurred in 4 (15.4%) patients, all due to periprocedural non-Q wave MI. Within one year, MACE occurred in 9 (34.6%) patients with 5 (19.2%) TLR.

RA for undilatable ISR with single or multiple stent layers was performed with favorable procedural outcomes and a relatively high MACE rate driven by TLR within one year.
RA for undilatable ISR with single or multiple stent layers was performed with favorable procedural outcomes and a relatively high MACE rate driven by TLR within one year.A 72-year-old male patient, with first degree atrioventricular block and LBBB on his baseline ECG, developed persistent complete atrioventricular block after recanalization of a chronic total occlusion of his left anterior descending artery (LAD) and ultimately underwent permanent pacemaker implantation. Occlusion of the second septal branch, probably supplying the right branch of the His bundle is speculated to have led to this complication. During elective intervention to the LAD territory in patients with prior conduction abnormalities on the ECG, care should be taken to preserve normal blood flow to the septal perforators. When a deterioration in septal perfusion occurs restoration of flow by wiring and balloon dilatation should be considered.Percutaneous intervention in the context of coronary artery ectasia (CAE) is penalized with no-reflow phenomenon. The glycoprotein-IIb/IIIa-inhibitor abciximab was the most accepted method for pharmacology thrombus resolution in this scenario, nevertheless, this agent was recently withdrawn. We describe 5 patients treated with local intracoronary fibrinolysis administrated through predesigned catheters in the setting of AMI and CAE.Approximately 45 million children participate in some form of athletics. The COVID-19 pandemic has affected many aspects of their lives, including sports activities. Families are asking care givers questions about how best to ensure the safety of their children when returning to sports activities. The American Academy of Pediatrics has issued revised guidelines for children returning to athletic activities after COVID-19. These include strengthening the recommendations for cloth mask wearing for all children engaging in vigorous sports and clarifications of cardiac risks to children who have had COVID-19.
To compare the diagnostic power of CT scan to a combination of exploratory laparoscopy (EXL) and CT scan in patients with stage IIIC-IV Ovarian Cancer (OC) by anatomic areas. To investigate if adding EXL to CT can reduce unnecessary laparotomy.

In the period 2009-2017, 350 consecutive patients with FIGO Stage IIIC-IV OC underwent CT and EXL prior to Visceral-Peritoneal debulking (VPD) and were included in the study. Radiologist and surgeons filled an ad-hoc form to report CT scan and EXL of eleven key anatomic areas. The decision to proceed to EXL was based on the CT scan and the decision to proceed to laparotomy (LPT) on CT and EXL. Setting LPT findings as the gold standard, positive and negative predictive value (PPV/NPV), sensitivity, specificity, and accuracy of CT, EXL and CT+EXL were calculated. We broke down the diagnostic outcomes by anatomic areas and determined the rate of unnecessary laparotomy avoided with the findings of EXL.

Median time for the EXL was 14min (SD +/- 3). No complication relreased by almost 60%.
To identify clinicopathological characteristics, treatment patterns, clinical outcomes and prognostic factors in patients with vulvar melanoma (VM).

This retrospective multicentre cohort study included 198 women with VM treated in eight cancer centres in the Netherlands and UK between 1990 and 2017. Clinicopathological features, treatment, recurrence, and survival data were collected. Overall and recurrence-free survival was estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariable Cox regression analysis.

The majority of patients (75.8%) had localized disease at diagnosis. VM was significantly associated with high-risk clinicopathological features, including age, tumour thickness, ulceration, positive resection margins and involved lymph nodes. Overall survival was 48% (95% CI 40-56%) and 31% (95% CI 23-39%) after 2 and 5 years respectively and did not improve in patients diagnosed after 2010 compared to patients diagnosed between 1990 and 2009. Recurrence occurrerapies to improve clinical outcomes in these aggressive tumours. Clinical trials with immunotherapy or targeted therapy in patients with high-risk, advanced or metastatic disease are highly needed.
To assess the cancer risk in a cohort of women with newly diagnosed endometriosis.

This retrospective, nationwide, population-based cohort study utilized data from the 10-year claims database of the Korean National Health Insurance from January 2008 to December 2018. Patients diagnosed with endometriosis between 2010 and 2013 were included; those who underwent appendectomy but were not diagnosed with endometriosis during the study period served as controls. No participant was diagnosed with cancer before enrollment. Cancer diagnoses according to the International Classification of Diseases, 10th revision, were compared between the two groups. Cancer occurrence in both groups was identified according to the diagnostic codes for different organ sites.

Altogether, 179,865 patients with endometriosis and 87,408 controls were analyzed, and the incidence rates of cancer were 644.3 and 543.8 per 100,000 person-years, respectively. Patients with endometriosis had a significantly increased overall cancer risk (hted in those with endometriosis.
To evaluate the outcomes of high-risk (HR) HPV-positive and -negative women affected by high-grade cervical dysplasia.

This is a retrospective multi-institutional study. Medical records of consecutive patients with high-grade cervical dysplasia undergoing conization between 2010 and 2014 were retrieved. All patients included had at least 5years of follow-up. A propensity-score matching was adopted in order to reduce the presence of confounding factors between groups. Kaplan-Meir and Cox hazard models were used to estimate 5-year outcomes.

Overall, data of 2966 women, affected by high-grade cervical dysplasia were reviewed. The study population included 1478 (85%) and 260 (15%) women affected by HR-HPV-positive and HR-HPV-negative high-grade cervical dysplasia. The prevalence of CIN2 and CIN3 among the HR-HPV-positive and -negative cohort was similar (p=0.315). Patients with HR-HPV-positive high-grade cervical dysplasia were at higher risk of 5-year recurrence (after primary conization) that HR-HPV-negative patients (p<0.001, log-rank test). Via multivariate analysis, HR-HPV-negative women were at low risk of recurrence (HR 1.69 (95%CI 1.05, 4.80); p=0.018, Cox Hazard model). A propensity-score matched comparison was carried out in order to reduce biases that are related to the retrospective study design. In comparison to HR-HPV-negative patients, thosewith HR-HPV-positive CIN3 was associate with a 8-fold increase in the risk of recurrence (p<0.001, log-rank test).

HR-HPV-negative high-grade cervical dysplasia is not uncommon, accounting for 15% of our study population. Those patients experience more favorable outcomes than patients with documented HR-HPV infection(s). Further prospective studies are needed to corroborate our data.
HR-HPV-negative high-grade cervical dysplasia is not uncommon, accounting for 15% of our study population. Those patients experience more favorable outcomes than patients with documented HR-HPV infection(s). Further prospective studies are needed to corroborate our data.While analytical methods targeting specific compounds are critical for food safety, analytes excluded from the targeted list will not be identified. Non-targeted analyses (NTA) using LC/HR-MS complement these approaches by producing information-rich data sets where molecular formula can be generated for each detected compound; however, data mining can be labor intensive. Thus, we examined different NTA approaches to reduce the number of compounds needing further investigation, without relying on a suspect list or MS/MS database, both in single ingredient foods (i.e., oats) and more complex, oat-containing samples. We investigated inherent sample variability and utilized this information to build in-house databases for removing food compounds from sample data. While food databases were useful for data reduction, differential analysis was the most promising approach for single ingredient foods because it substantially reduced the number of features while retaining spiked QC compounds; however, a combination of approaches was necessary with greater sample complexity.Vulnerable Child Syndrome (VCS) occurs in the setting in which a child recovers from a life-threatening illness, as result of which the parent develops heightened parental perceptions of child vulnerability (PPCV). This leads to a pattern of overprotective parenting which may result in adverse neurodevelopmental and behavioral outcomes in the child over time. Parents of premature infants have been shown to be at increased risk of developing raised PPCV while their infants may develop symptoms of VCS. The PreVNT trial is a randomized controlled trial designed to test the efficacy of a 5-session manualized Cognitive Behavioral Therapy (CBT) intervention to reduce PPCV. Results of a pilot study of parents of premature infants (n = 41) demonstrate that the intervention can be delivered with high ratings of treatment fidelity and with a completion rate of 100% during the NICU admission, and 78% at 6 months post term. Ratings of parental satisfaction ranged between 4.9 and 5 out of 5 demonstrating high satisfaction with the intervention. Pilot feasibility and maternal satisfaction data are presented for a group of 22 intervention families, which suggest a CBT model for understanding VCS is feasible and deemed helpful by parents. This review is gauged to summarize risk of VCS development, diagnosis of VCS, and effective treatments for VCS through Cognitive Behavioral Therapy. We also present a paradigm shift in a therapeutic approach by introducing the PreVNT Trial. Given that VCS can interfere with the long-term outcomes of both infant and family, it is important to understand VCS and address its involvement in NICU and post NICU discharge care. Further research is needed in this area.
Regulatory agencies are responsible for defining the use of off-label (OL) and unlicensed (UL) drug prescription in neonatal intensive care. However, these regulatory criteria may differ between agencies in different countries. The aim of this study was to establish the frequency of OL and UL drug prescription in a sample of patients in a neonatal intensive care unit applying the criteria of the Food and Drug Administration (FDA) of the United States and the Agência Nacional de Vigilância Sanitária (ANVISA) of Brazil, analysing the differences observed in the results based on the applied criteria.

Prospective cohort study in neonates admitted for more than 24hours to the neonatal intensive care unit (NICU) of a teaching maternity hospital between August 2017 and July 2018. We obtained information concerning the drugs included in the analysis of OL and UL prescriptions from the DrugDex-Micromedex® and official information on pharmaceutical products in Brazil. We used the kappa correlation coefficient to asnt in neonatal intensive care applying the criteria of either agency, although the FDA has established more detailed criteria in terms of the ages and indications for which prescription is authorised.
Individuals with diabetes have a high risk of cardiovascular disease (CVD). However, the association between type 1 diabetes mellitus (T1DM) and the risk of CVD has not been well addressed. This meta-analysis aimed to investigate the association between T1DM and CVD.

We searched the PubMed and EMBASE for studies that examined the association between T1DM and CVD until October 2020. We calculated the pooled risk ratios (RRs) with confidence intervals (CIs) from individual studies based on a random-effects model.

We included 10 observational studies involving 166,027 patients with T1DM, and individuals were matched controls from the general population. Among T1DM patients, the RR of CVD was 5.09 (95% CI, 3.72-6.96), of coronary heart disease (CHD) was 9.38 (95% CI, 5.56-15.82), and of myocardial infarction was 6.37 (95% CI, 3.81-10.66). The RR of heart failure was 4.29 (95% CI, 3.54-5.19), of atrial fibrillation was 1.36 (95% CI, 1.17-1.59), and of stroke was 4.08 (95% CI, 3.42-4.86). Moreover, there was an increased RR among females for CHD, CVD, myocardial infarction, and stroke associated with T1DM.

This study suggests that T1DM is associated with an increased risk of several types of CVD. However, the possible mechanisms for the increased risk of CVD remain unclear.
This study suggests that T1DM is associated with an increased risk of several types of CVD. However, the possible mechanisms for the increased risk of CVD remain unclear.Pericardial Decompression Syndrome (PDS) is an uncommon but life-threatening complication following pericardiocentesis for cardiac tamponade. We report PDS after pericardiocentesis in two patients that presented to the emergency department with cardiac tamponade. In both cases, pericardiocentesis was performed under ultrasound guidance using the left parasternal approach and approximately 1200-1500 mL of pericardial fluid was removed. Immediately after pericardiocentesis, the haemodynamic status of the patients improved. However, 2-3 h post decompression, both patients developed hypotension and pulmonary edema with reduced left ventricular function, suggestive of PDS. PDS is a condition that is described as paradoxical worsening of vital signs after successful decompression of the pericardium in the setting of acute tamponade. Three possible mechanisms explaining PDS are ischaemic, hemodynamic and autonomic processes. If PDS is unrecognized and untreated, it is associated with a high mortality rate secondary to pulmonary edema and cardiogenic shock.
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