Ago2/CAV1 interaction potentiates metastasis via controlling Ago2 localization and miRNA action.

Ago2 differentially regulates oncogenic and tumor-suppressive miRNAs in cancer cells. This discrepancy suggests a secondary event regulating Ago2/miRNA action in a context-dependent manner. We show here that a positive charge of Ago2 K212, that is preserved by SIR2-mediated Ago2 deacetylation in cancer cells, is responsible for the direct interaction between Ago2 and Caveolin-1 (CAV1). Through this interaction, CAV1 sequesters Ago2 on the plasma membranes and regulates miRNA-mediated translational repression in a compartment-dependent manner. Ago2/CAV1 interaction plays a role in miRNA-mediated mRNA suppression and in miRNA release via extracellular vesicles (EVs) from tumors into the circulation, which can be used as a biomarker of tumor progression. Increased Ago2/CAV1 interaction with tumor progression promotes aggressive cancer behaviors, including metastasis. Ago2/CAV1 interaction acts as a secondary event in miRNA-mediated suppression and increases the complexity of miRNA actions in cancer.

Urinary heavy metals and attention-deficit/hyperactivity symptoms of preschool children: a mixed-exposure analysis.

The neurotoxic effects of certain heavy metals are well established, but only a few studies have investigated the joint effect of concurrent exposure to multiple ones. The study aims to evaluate the association between mixed exposure to neurotoxic metals and the psychosocial behavior of preschool children. Using a stratified sampling strategy, we recruited participants from 105 kindergartens in 41 townships of Taiwan and excluded those with blood lead levels ≥ 3.5 µg/L. The first-morning void urines were collected and analyzed for cadmium, manganese, arsenic, chromium, lead, and nickel concentrations using inductively coupled plasma mass spectrometry. We applied the parentally reported Strengths and Difficulties Questionnaire (SDQ) and Swanson, Nolan, and Pelham IV (SNAP-IV) scales to evaluate the psychosocial behaviors. Multiple linear regressions were utilized to evaluate the associations between each heavy metal and the outcomes, while the mixed effect of concurrent exposure was estimated by using a Quantile g-computation approach. A total of 977 preschool children were included in the study, and the mean (SD) age was 5.7 (0.7) years old. In single pollutant models, we observed adverse effects of urinary manganese, nickel, arsenic, and lead on the specific subsets of SDQ. Furthermore, the combined effect of six heavy metals significantly affected the hyperactivity/inattention symptoms (beta = 0.46, 95% CI: 0.13-0.78, with all metals increased by one quartile), and chromium and lead were the two major contributors. Similar detrimental effects of urinary cadmium and lead were also observed in the SNAP-IV subsets, although the joint effect analysis was not significant. The study provided evidence that concurrent exposure to multiple heavy metals may exert increased risks of hyperactivity/inattention in children compared to single pollutant exposure. Further studies are needed to verify our findings regarding mixed exposure to multiple neurotoxic metals.

Preferences for long-acting pre-exposure prophylaxis among gay, bisexual and other men who have sex with men in Taiwan: findings from the 2021 HEART Survey.

INTRODUCTION: While various antiretrovirals have been studied as potential candidates for long-acting pre-exposure prophylaxis (PrEP), the bimonthly injectable cabotegravir-the first long-acting form of PrEP-was approved in 2021. Event-driven (ED) PrEP has been the most prevalent dosing regimen among gay, bisexual and other men who have sex with men (GBMSM) in Taiwan, providing a unique setting to observe the preferences for long-acting PrEP in a community where the daily regimen is not the mainstream method. This study aimed to determine the preferences for the different forms and dosing intervals of long-acting PrEP that are currently in the development pipeline. METHODS: We conducted a survey in 2021 by convenience sampling the users of social networking applications for GBMSM in Taiwan. Our survey included questions on sexual behaviours, current PrEP regimens and the preferences for potential candidates of long-acting PrEP, such as implants, intramuscular and subcutaneous injections. We compared the Likert-scale preference ratings for potential long-acting options, and conducted logistic regression analysis to examine the factors associated with a preference for bimonthly intramuscular injections (2M IM) over ED and daily PrEP regimens, respectively. RESULTS: A total of 1728 responses were eligible for analysis. Three percent of respondents (n = 52) were daily PrEP users; 11.5% (n = 198) were ED PrEP users. When not considering cost, current PrEP users-regardless of their original dosing regimen-were most likely to express preferences for monthly oral PrEP, followed by a 6-month subcutaneous injectable (6M SC) and 2M IM. However, among non-current PrEP users, monthly oral PrEP was the most preferred form, followed by ED, daily oral and 6M SC injectable. Multivariable logistic regression revealed that current daily users, those willing to take PrEP in the next 6 months and those with more sex partners in the last 12 months had a significant correlation with preferences for the 2M IM injectable over the ED PrEP. CONCLUSIONS: The monthly oral form was the most preferable long-acting PrEP among GBMSM in Taiwan. Current daily PrEP users preferred the 2M IM injectable over the ED PrEP, which made the 2M IM injectable a potential alternative. Further studies should focus on how the cost and delivery affect PrEP preferences and their actual uptake.

Untargeted metabolomics analysis assisted by signal selection for comprehensively identifying metabolites of new psychoactive substances: 4-MeO-α-PVP as an example.

New psychoactive substances (NPS) have been rapidly emerged as legal alternatives to controlled drugs, which raised severe public health issue. The detection and monitoring of its intake by complete metabolic profiling is an urgent and vital task. Untargeted metabolomics approach has been applied for several NPS metabolites studies. Although the number of such works is relatively limited but with a rapidly growing need. The present study aimed to propose a procedure that includes liquid chromatography high-resolution mass spectrometry (LC-HRMS) analysis and a signal selection software, MetaboFinder, programed as a web tool. The comprehensive metabolites profile of one kind of NPS, 4-methoxy-α-pyrrolidinovalerophenone (4-MeO-α-PVP), was studied by using this workflow. In this study, two different concentrations of 4-MeO-α-PVP along with as blank sample were incubated with human liver S9 fraction for the conversion to their metabolites and followed by LC-MS analysis. After retention time alignment and feature identification, 4640 features were obtained and submitted to statistical analysis for signal selection by using MetaboFinder. A total of 50 features were considered as 4-MeO-α-PVP metabolite candidates showing significant changes (p < 0.00001 and fold change >2) between the two investigated groups. Targeted LC-MS/MS analysis was conducted focusing on these significantly expressed features. Assisted by chemical formula determination according to high mass accuracy and in silico MS2 fragmentation prediction, 19 chemical structure identifications were achieved. Among which, 8 metabolites have been reported derived from 4-MeO-α-PVP in a previous literature while 11 novel 4-MeO-α-PVP metabolites were identified by using our strategy. Further in vivo animal experiment confirmed that 18 compounds were 4-MeO-α-PVP metabolites, which demonstrated the feasibility of our strategy for screening the 4-MeO-α-PVP metabolites. We anticipate that this procedure may support and facilitate traditional metabolism studies and potentially being applied for routine NPS metabolites screening.

Screening Chest CT Prior to Allogenic Hematopoietic Stem Cell Transplantation.

Pulmonary complications constitute a major cause of morbidity and mortality in the post-allogenic hematopoietic stem cell transplantation (alloHSCT) period. Although chest X-ray (CXR) is customarily used for screening, we have used chest computed tomography (CT) scans. To characterize the prevalence of abnormalities and explore their impact on alloHSCT eligibility and outcomes post-transplantation, we conducted a retrospective analysis using real-world data collected at our center for adult patients who were evaluated for alloHSCT between January 2013 and December 2020 and identified 511 eligible patients. The most common primary disease was acute myeloid leukemia, in 49% of patients, followed by myelodysplastic syndrome (23%), lymphoma (11%), and acute lymphocytic leukemia (10%). Abnormal screening chest CT results were found in 199 patients (39%). The most frequent detected abnormality was pulmonary nodule, in 78 patients (35%), followed by consolidation in 42 (19%), ground-glass opacification in 33 (15%), bronchitis and bronchiolitis in 25 (11%), pleural effusions in 14 (6%), and new primary cancer in 7 (2%). CXR detected abnormalities in only approximately one-half of the patients (48%) with an abnormal chest CT scan. Among the 199 patients with an abnormal chest CT scan, 98 (49%) underwent further assessment and/or intervention before transplantation. The most common workup was pulmonary consultation in 32%, followed by infectious diseases consultation in 24%. Lung biopsy was obtained in 20%, and antimicrobial therapy was initiated after confirming an infection diagnosis in 20%. Patients with an abnormal chest CT scan demonstrated worse overall survival (P = .032), nonrelapse mortality (P = .015), and pulmonary-related mortality (P < .001) compared to those with a normal chest CT scan. Our study suggests that pretransplantation screening chest CT is beneficial in uncovering invasive infections and underlying malignancies and allows for appropriate interventions before alloHSCT to prevent potentially serious post-transplantation complications without causing a delay in alloHSCT. Nevertheless, abnormal CT findings prior to transplantation may be associated with overall worse prognosis.

Connecting chemical exposome to human health using high-resolution mass spectrometry-based biomonitoring: Recent advances and future perspectives.

Compared with the rapid advances in genomics leading to broad understanding of human disease, the linkage between chemical exposome and diseases is still under investigation. High-resolution mass spectrometry (HRMS) is expected to accelerate the process via relatively accurate and precise biomonitoring of human exposome. This review covers recent advancements in biomonitoring of exposed environmental chemicals (chemical exposome) using HRMS described in the 124 articles that resulted from a systematic literature search on Medline and Web of Science databases. The analytical strategic aspects, including the selection of specimens, sample preparation, instrumentation, untargeted versus targeted analysis, and workflows for MS-based biomonitoring to explore the environmental chemical space of human exposome, are deliberated. Applications of HRMS in human exposome investigation are presented by biomonitoring (1) exposed chemical compounds and their biotransformation products; (2) DNA/protein adducts; and (3) endogenous compound perturbations. Challenges and future perspectives are also discussed.

Combating multidrug-resistant Helicobacter pylori with moenomycin A in combination with clarithromycin or metronidazole.

Current treatment of Helicobacter pylori involves a triple therapy comprising one proton pump inhibitor and two other antibiotics; however, the outcomes are limited due to the existence of antibiotic resistant strains. We previously reported that moenomycin A, a cell-wall transglycosylase inhibitor, is highly active against multidrug-resistant Helicobacter pylori. Herein we show that combination of moenomycin A with the protein synthesis inhibitor clarithromycin or metronidazole can synergistically achieve almost 95% eradication of multidrug-resistant Helicobacter pylori. We also found that the moenomycin A-non-susceptible strains of Helicobacter pylori with deletion of transglycosylase exhibit moenomycin A hyposensitivity, faster growth and impaired biofilm formation compared to the parental strain. Overall, the combination of moenomycin A and clarithromycin or metronidazole to achieve a synergistic effect on different targets is a promising treatment for multidrug-resistant Helicobacter pylori.

Predictors of Covid-19 Vaccination Response After In-Vivo T-Cell-Depleted Stem Cell Transplantation.

Covid-19 vaccination is recommended in allogeneic transplant recipients, but many questions remain regarding its efficacy. Here we studied serologic responses in 145 patients who had undergone allogeneic transplantation using in vivo T-cell depletion. Median age was 57 (range 21-79) at transplantation and 61 (range 24-80) at vaccination. Sixty-nine percent were Caucasian. One third each received transplants from HLA-identical related (MRD), adult unrelated (MUD), or haploidentical-cord blood donors. Graft-versus-host disease (GVHD) prophylaxis involved in-vivo T-cell depletion using alemtuzumab for MRD or MUD transplants and anti-thymocyte globulin for haplo-cord transplants. Patients were vaccinated between January 2021 and January 2022, an average of 31 months (range 3-111 months) after transplantation. Sixty-one percent received the BNT162b2 (bioNtech/Pfizer) vaccine, 34% received mRNA-1273 (Moderna), and 5% received JNJ-78436735 (Johnson & Johnson). After the initial vaccinations (2 doses for BNT162b2 and mRNA-1273, 1 dose for JNJ-7843673), 124 of the 145 (85%) patients had a detectable SARS-CoV-2 spike protein (S) antibody, and 21 (15%) did not respond. Ninety-nine (68%) had high-level responses (≥100 binding antibody units [BAU]/mL)m and 25 (17%) had a low-level response (<100 BAU/mL). In multivariable analysis, lymphocyte count less than 1 × 109/ mL, having chronic GVHD, and being vaccinated in the first year after transplantation emerged as independent predictors for poor response. Neither donor source nor prior exposure to rituximab was predictive of antibody response. SARS-CoV-2 vaccination induced generally high response rates in recipients of allogeneic transplants including recipients of umbilical cord blood transplants and after in-vivo T cell depletion. Responses are less robust in those vaccinated in the first year after transplantation, those with low lymphocyte counts, and those with chronic GVHD.

Simultaneous determination of eight ß-adrenergic agonists in human urine by an isotope dilution-online clean-up system coupled with liquid chromatography-tandem mass spectrometry.

ß-Adrenergic agonist compounds are medicines that open up the lung's medium and large airways. ß-Adrenergic agonist compounds have been illegally or legally used to increase lean muscle mass in meat animals, bodybuilding, weight-loss programs, and athletes. Developing a rapid analytical approach for determining ß-adrenergic agonist compounds in biological samples is crucial for individual exposure assessment. This study established an analytical method for simultaneously measuring eight ß-adrenergic agonist compounds in human urine, including clenbuterol, terbutaline, salbutamol, ractopamine, zilpaterol, cimaterol, tulobuterol, and fenoterol. Two hundred microliters of a urine sample were added to eight deuterium-labeled internal standard mixtures and glucuronidase/arylsulfatase for enzymatic hydrolysis, and were then analyzed using an online clean-up system coupled with a liquid chromatography-tandem mass spectrometry system (LC-MS/MS). The limit of quantification ranged from 0.03 to 0.12 ng/mL urine for the eight ß-adrenergic agonist compounds. The relative standard deviations (RSD) of the within-run and between-run precisions were less than 10%, and the relative accuracy errors were less than 17% in the three-level spiked artificial urine samples. Two hundred eighty human urine samples collected from the general population in Taiwan were assessed to demonstrate the capability and feasibility of this method. The detection frequencies were 33% for clenbuterol, 5% for ractopamine, and less than 5% for the others. We concluded that the isotope dilution-online clean-up system coupled with LC-MS/MS method is a valuable analytical method for investigating urinary ß-adrenergic agonist compounds in humans and is valuable for human biomonitoring studies.

Axicabtagene Ciloleucel in Patients Ineligible for ZUMA-1 Because of CNS Involvement and/or HIV: A Multicenter Experience.

Secondary central nervous system lymphoma (SCNSL) is associated with poor prognosis and new therapeutic approaches are needed. The pivotal trial that led to US Food and Drug Administration (FDA) approval of axicabtagene ciloleucel excluded patients with SCNSL and human immunodeficiency virus. In this multi-institutional retrospective study, 14 SCNSL patients treated with axicabtagene ciloleucel, 3 of whom had human immunodeficiency virus, experienced rates of severe neurotoxicity and complete response of 32% and 58%, respectively. This is similar to rates observed in the pivotal ZUMA-1 trial that led to the approval of axi-cel at median follow-up of 5.9 months. Chimeric antigen receptor T-cell therapy is potentially a life-saving therapy for SCNSL patients and should not be withheld.

Exploration of long-term exposure markers for phthalate esters in human hair using liquid chromatography-tandem mass spectrometry.

Phthalate esters are a group of synthetic industrial chemicals that are widely used in plastics. Urinary phthalate metabolites are short-term exposure markers frequently used to represent exposure levels in environmental epidemiology studies. Human hair is an alternative matrix for recording long-term exposure, but there are still analytical challenges that need to be addressed. In this study, an analytical method was established for simultaneously measuring nine major phthalate metabolites in human hair and successfully applied to measure phthalate metabolites in 30 hair samples collected from 30 individual human volunteers without known occupational exposure to phthalates. Two portions of 25 mg of hair samples were extracted by acidified methanol and water in 240 min of ultrasonication and then analyzed using a liquid chromatography-tandem mass spectrometry system. The limit of quantification ranged from 0.72 to 10.7 ng/g hair for nine phthalate metabolites. All nine phthalate metabolites were detected in more than 70% of the 30 individual human hair samples. The measured levels of hair phthalate metabolites were (in descending order): MEHP > MMP â‰« MEP > MBP (MnBP + MiBP) > MiNP > MEHHP ≈ MEOHP ≈ MECPP. The primary metabolite, MEHP (692 ± 582 ng/g), is the major DEHP metabolite in hair. This result is consistent with the findings in blood but not in urine, in which the secondary metabolites are the major DEHP metabolites. This method is easy to foresee with a clinical application and applies to human biomonitoring studies to assess long-term environmental phthalate exposure.

Erinacine A Prevents Lipopolysaccharide-Mediated Glial Cell Activation to Protect Dopaminergic Neurons against Inflammatory Factor-Induced Cell Death In Vitro and In Vivo.

Hericium erinaceus (HE) is a common edible mushroom consumed in several Asian countries and considered to be a medicinal mushroom with neuroprotective effects. Erinacine A (EA) is a bioactive compound in Hericium erinaceus mycelium (HEM) that has been shown to have a neuroprotective effect against neurodegenerative diseases, e.g., Parkinson's disease (PD). Although the etiology of PD is still unclear, neuroinflammation may play an important role in causing dopaminergic neuron loss, which is a pathological hallmark of PD. However, glial cell activation has a close relationship with neuroinflammation. Thus, this study aimed to investigate the anti-neuroinflammatory and neuroprotective effects of EA on lipopolysaccharide (LPS)-induced glial cell activation and neural damage in vitro and in vivo. For the in vitro experiments, glial cells, BV-2 microglial cells and CTX TNA2 astrocytes were pretreated with EA and then stimulated with LPS and/or IFN-γ. The expression of proinflammatory factors in the cells and culture medium was analyzed. In addition, differentiated neuro-2a (N2a) cells were pretreated with EA or HEM and then stimulated with LPS-treated BV-2 conditioned medium (CM). The cell viability and the amount of tyrosine hydroxylase (TH) and mitogen-activated protein kinases (MAPKs) were analyzed. In vivo, rats were given EA or HEM by oral gavage prior to injection of LPS into the substantia nigra (SN). Motor coordination of the rats and the expression of proinflammatory mediators in the midbrain were analyzed. EA pretreatment prevented LPS-induced iNOS expression and NO production in BV-2 cells and TNF-α expression in CTX TNA2 cells. In addition, both EA and HEM pretreatment significantly increased cell viability and TH expression and suppressed the phosphorylation of JNK and NF- κB in differentiated N2a cells treated with CM. In vivo, both EA and HEM significantly improved motor dysfunction in the rotarod test and the amphetamine-induced rotation test and reduced the expression of TNF-α, IL-1ß and iNOS in the midbrain of rats intranigrally injected with LPS. The results demonstrate that EA ameliorates LPS-induced neuroinflammation and has neuroprotective properties.

Adenovirus viremia after in vivo T-cell depleted allo-transplant in adults: low lymphocyte counts are associated with uncontrolled viremia and fatal outcomes.

The incidence of adenovirus viremia and the role of screening in preventing adenovirus disease in adult transplant recipients are not well defined. Between January 2017 and May 2020, 262 allogeneic transplants were performed using in vivo T-cell depletion. Adenovirus viremia was found in 59 patients for a cumulative incidence of 10% by one hundred days and 23% (95% CI 20-26%) by one year. There was a higher incidence of viremia associated with cord blood transplant (p = .04). No other patient, donor or transplant characteristics were identified that predicted for viremia. In 47 patients (80%), viremia remained well below 200,000 copies/mL and resolved. Twelve patients developed high level viremia. Treatment with antivirals and in some cases adoptive cell therapy, was often ineffective and only two survived. Low lymphocyte count at initial detection of adenovirus viremia was the best predictor of uncontrolled disease.

The efficacy of Lactobacillus acidophilus and rhamnosus in the reduction of bacterial load of Helicobacter pylori and modification of gut microbiota-a double-blind, placebo-controlled, randomized trial.

BACKGROUND: Probiotics may alter the gut microbiota and may reduce antibiotic-related dysbiosis after H. pylori eradication. However, whether probiotics are effective in reducing the bacterial load of H. pylori and modifying the gut microbiota remains unknown. We aimed to assess the efficacy of Lactobacillus acidophilus and Lactobacillus rhamnosus in reducing the bacterial load of H. pylori and modifying the gut microbiota. MATERIALS AND METHODS: In this double-blind, randomized, placebo-controlled trial, we recruited 40 adult subjects with moderate to high bacterial loads of H. pylori, defined as a mean delta over baseline (DOB) value of the 13 C-urea breath test (13 C-UBT) of 10 or greater every 4 days 6 times. Eligible subjects were randomized in a 1:1 ratio to receive either probiotics containing Lactobacillus acidophilus and Lactobacillus rhamnosus or placebo twice daily for 4 weeks. 13 C-UBT was measured weekly from the beginning of treatment to 2 weeks after treatment. Amplification of the V3 and V4 hypervariable regions of the 16S rRNA was performed for fecal microbiota. RESULTS: A total of 40 subjects were randomized to receive probiotics or placebo. The DOB value was significantly lower in the probiotic group than in the placebo group after 4 weeks of treatment (26.0 vs. 18.5, p = .045). The DOB value was significantly reduced compared to that at baseline in the probiotic group (18.5 vs. 26.7, p = .001) but not in the placebo group (26.0 vs. 25.0, p = .648). However, the eradication rate for H. pylori was 0% in both groups. There was no significant difference in the DOB values between the two groups 1 and 2 weeks after discontinuation of the probiotics. There were also no significant changes observed in the α-diversity and ß-diversity at week 4 compared to baseline in the probiotic group (p = .77 and 0.91) and the placebo group (p = .26 and 0.67). CONCLUSIONS: Although the use of Lactobacillus acidophilus and Lactobacillus rhamnosus may reduce the bacterial load of H. pylori, there were no significant changes in the composition of gut microbiota. This trial is registered with ClinicalTrials.gov, NCT02725138.

Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. METHODS: In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0-1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing. FINDINGS: Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8-43·8), the overall response rate was 53·0% (95% CI 43·5-62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3-4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. INTERPRETATION: Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk-benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). FUNDING: Novartis Pharmaceuticals.

Health service and medication use of parents of childhood cancer survivors: a controlled comparison study.

BACKGROUND: Parents of childhood cancer survivors may be vulnerable to experiencing poor health outcomes, but little is known about how these parents use healthcare. This study investigated the nature and extent of survivors' parents' healthcare and medication use relative to a comparison group. We also examined whether demographic or cancer-related factors were related to healthcare use and whether healthcare use was associated with parents' general functioning. METHODS: We conducted a cross-sectional study involving 55 parents of cancer survivors recruited through eight Australian hospitals, and 135 parents of children without a cancer diagnosis, through an online recruitment platform. Participants responded to a questionnaire assessing their health service usage, regular medications, general functioning (engagement activities including work/study) and anxiety and depression symptoms (using PROMIS short forms). We performed regression analysis to determine factors related to healthcare and medication use in parents of survivors. RESULTS: More parents of survivors reported accessing mental health services than comparison parents (56% vs. 33%, p=.003), mainly due to their use of social workers. Fewer parents of survivors reported accessing other community health services, particularly general practitioners (51% vs. 78%, p<.001). Having a child survivor who was male was associated with greater use of community health services (B= -0.67, p=.008). No other demographic or cancer-related variables were associated with health service use. Health service use was not associated with general functioning, but greater medication use was associated with higher anxiety scores (B = 1.41, p=.008). CONCLUSION: Parents of childhood cancer survivors showed different patterns of health service use relative to comparison parents, but the extent of their use was not significantly linked with demographic or cancer-related variables. Comprehensive assessment of parents' needs in clinical encounters remains vital to identify and appropriately match support needs with available services.

Colonization With Fluoroquinolone-Resistant Enterobacterales Decreases the Effectiveness of Fluoroquinolone Prophylaxis in Hematopoietic Cell Transplant Recipients.

BACKGROUND: Levofloxacin prophylaxis is recommended to prevent gram-negative bloodstream infections (BSIs) in patients with prolonged chemotherapy-induced neutropenia. However, increasing fluoroquinolone resistance may decrease the effectiveness of this approach. METHODS: We assessed the prevalence of colonization with fluoroquinolone-resistant Enterobacterales (FQRE) among patients admitted for hematopoietic cell transplantation (HCT) from November 2016 to August 2019 and compared the risk of gram-negative BSI between FQRE-colonized and noncolonized patients. All patients received levofloxacin prophylaxis during neutropenia. Stool samples were collected upon admission for HCT and weekly thereafter until recovery from neutropenia, and underwent selective culture for FQRE. All isolates were identified and underwent antimicrobial susceptibility testing by broth microdilution. FQRE isolates also underwent whole-genome sequencing. RESULTS: Fifty-four of 234 (23%) patients were colonized with FQRE prior to HCT, including 30 of 119 (25%) allogeneic and 24 of 115 (21%) autologous HCT recipients. Recent antibacterial use was associated with FQRE colonization (P = .048). Ninety-one percent of colonizing FQRE isolates were Escherichia coli and 29% produced extended-spectrum ß-lactamases. Seventeen (31%) FQRE-colonized patients developed gram-negative BSI despite levofloxacin prophylaxis, compared to only 2 of 180 (1.1%) patients who were not colonized with FQRE on admission (P < .001). Of the 17 gram-negative BSIs in FQRE-colonized patients, 15 (88%) were caused by FQRE isolates that were genetically identical to the colonizing strain. CONCLUSIONS: Nearly one-third of HCT recipients with pretransplant FQRE colonization developed gram-negative BSI while receiving levofloxacin prophylaxis, and infections were typically caused by their colonizing strains. In contrast, levofloxacin prophylaxis was highly effective in patients not initially colonized with FQRE.