ABSTRACT
Lyme arthritis (LA) was recognized as a separate entity in 1975 because of geographic clustering of children often diagnosed with juvenile rheumatoid arthritis in Lyme, Connecticut. After identification of erythema migrans as a common early feature of the illness, a prospective study of such patients implicated Ixodes scapularis ticks in disease transmission. In 1982, the causative agent, now called Borrelia burgdorferi, was cultured from these ticks and from Lyme disease patients. Subsequently, it was shown that LA could usually be treated successfully with oral antibiotics but sometimes required intravenous antibiotics. Yet, a small percentage of patients developed a dysregulated, proinflammatory immune response leading to persistent postinfectious synovitis with vascular damage, cytotoxic and autoimmune responses, and fibroblast proliferation, a lesion similar to that of rheumatoid arthritis. The message from postinfectious LA for other autoimmune arthritides is that a complex immune response with autoimmune features can begin with a microbial infection.
Subject(s)
Lyme Disease , Lyme Disease/immunology , Humans , Animals , History, 20th Century , Borrelia burgdorferi/immunology , History, 21st Century , Anti-Bacterial Agents/therapeutic use , Ixodes/microbiologyABSTRACT
BACKGROUND: There is a paucity of high-quality evidence based on clinical endpoints for routine cleaning of shared medical equipment. We assessed the effect of enhanced cleaning and disinfection of shared medical equipment on health-care-associated infections (HAIs) in hospitalised patients. METHODS: We conducted a stepped-wedge, cluster randomised, controlled trial in ten wards of a single hospital located on the central coast of New South Wales, Australia. Hospitals were eligible for inclusion if they were classified as public acute group A according to the Australian Institute of Health and Welfare, were located in New South Wales, had an intensive care unit, had a minimum of ten wards, and provided care for patients aged 18 years or older. Each cluster consisted of two randomly allocated wards (by use of simple randomisation), with a new cluster beginning the intervention every 6 weeks. Wards were informed of their allocation 2 weeks before commencement of intervention exposure, and the researcher collecting primary outcome data and audit data was masked to treatment sequence allocation. In the control phase, there was no change to environmental cleaning practices. In the intervention phase, a multimodal cleaning bundle included an additional 3 h per weekday for the dedicated cleaning and disinfection of shared medical equipment by 21 dedicated cleaning staff, with ongoing education, audit, and feedback. The primary outcome was the number of confirmed cases of HAI, as assessed by a fortnightly point prevalence survey and measured in all patients admitted to the wards during the study period. The completed trial is registered with Australia New Zealand Clinical Trials Registry (ACTRN12622001143718). FINDINGS: The hospital was recruited on July 31, 2022, and the study was conducted between March 20 and Nov 24, 2023. We assessed 220 hospitals for eligibility, of which five were invited to participate, and the first hospital to formally respond was enrolled. 5002 patients were included in the study (2524 [50·5%] women and 2478 [49·5%] men). In unadjusted results, 433 confirmed HAI cases occurred in 2497 patients (17·3%, 95% CI 15·9 to 18·8) in the control phase and 301 confirmed HAI cases occurred in 2508 patients (12·0%, 10·7 to 13·3) in the intervention phase. In adjusted results, there was a relative reduction of -34·5% (-50·3 to -17·5) in HAIs following the intervention (odds ratio 0·62, 95% CI 0·45 to 0·80; p=0·0006), corresponding to an absolute reduction equal to -5·2% (-8·2 to -2·3). No adverse effects were reported. INTERPRETATION: Improving the cleaning and disinfection of shared medical equipment significantly reduced HAIs, underscoring the crucial role of cleaning in improving patient outcomes. Findings emphasise the need for dedicated approaches for cleaning shared equipment. FUNDING: National Health and Medical Research Council.
ABSTRACT
The development of resistance to current standard-of-care treatments, such as androgen receptor (AR) targeting therapies, remains a major challenge in the management of advanced prostate cancer. There is an urgent need for therapeutic strategies targeting key resistance drivers, such as AR variants like AR-V7 and steroidogenic enzymes like AKR1C3, to improve outcomes for patients with advanced prostate cancer. Here, we designed, synthesized, and characterized a class of LX compounds targeting both AR/AR variants and AKR1C3. Molecular docking indicated that LX compounds bound to the AKR1C3 active sites. LX1 blocked AKR1C3 enzymatic activity, suppressing the conversion of androstenedione into testosterone. LX compounds also reduced AR/AR-V7 expression and downregulated their target genes. In vitro, LX1 inhibited the growth of prostate cancer cells resistant to antiandrogens, including enzalutamide, abiraterone, apalutamide, and darolutamide. Treatment with LX1 in vivo significantly decreased tumor growth, lowered serum PSA levels, and reduced intratumoral testosterone levels, without affecting mouse body weight. Furthermore, LX1 overcame resistance to enzalutamide treatment, and the combination of LX1 with enzalutamide further suppressed tumor growth. Collectively, the dual effect of LX1 in reducing intratumoral testosterone and AR signaling, along with its synergy with standard therapies in resistant models, underscores its potential as a valuable treatment option for advanced prostate cancer.
ABSTRACT
N-Myc is a key driver of neuroblastoma and neuroendocrine prostate cancer (NEPC). One potential way to circumvent the challenge of undruggable N-Myc is to target the protein homeostasis (proteostasis) system that maintains N-Myc levels. Here, we identify heat shock protein 70 (HSP70) as a top partner of N-Myc, which binds a conserved "SELILKR" motif and prevents the access of E3 ubiquitin ligase, STIP1 homology and U-box containing protein 1 (STUB1), possibly through steric hindrance. When HSP70's dwell time on N-Myc is increased by treatment with the HSP70 allosteric inhibitor, STUB1 is in close proximity with N-Myc and becomes functional to promote N-Myc ubiquitination on the K416 and K419 sites and forms polyubiquitination chains linked by the K11 and K63 sites. Notably, HSP70 inhibition significantly suppressed NEPC tumor growth, increased the efficacy of aurora kinase A (AURKA) inhibitors, and limited the expression of neuroendocrine-related pathways.
Subject(s)
HSP70 Heat-Shock Proteins , Prostatic Neoplasms , Proteostasis , Ubiquitin-Protein Ligases , Ubiquitination , Male , Humans , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/genetics , HSP70 Heat-Shock Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitination/drug effects , Cell Line, Tumor , Animals , Aurora Kinase A/metabolism , Aurora Kinase A/genetics , Aurora Kinase A/antagonists & inhibitors , N-Myc Proto-Oncogene Protein/metabolism , N-Myc Proto-Oncogene Protein/genetics , Mice , Carcinoma, Neuroendocrine/metabolism , Carcinoma, Neuroendocrine/genetics , Carcinoma, Neuroendocrine/drug therapy , Carcinoma, Neuroendocrine/pathology , Neuroendocrine Tumors/metabolism , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/pathologyABSTRACT
Macrocyclic peptides show promise in targeting high-value therapeutically relevant binding sites due to their high affinity and specificity. However, their clinical application is often hindered by low membrane permeability, which limits their effectiveness against intracellular targets. Previous studies focused on peptide conformations in various solvents, leaving a gap in understanding their interactions with and translocation through lipid bilayers. Addressing this, our study explores the membrane interactions of stapled peptides, a subclass of macrocyclic peptides, using solid-state nuclear magnetic resonance (ssNMR) spectroscopy and molecular dynamics (MD) simulations. We conducted ssNMR measurements on ATSP-7041M, a prototypical stapled peptide, to understand its interaction with lipid membranes, leading to an MD-informed model for peptide membrane permeation. Our findings reveal that ATSP-7041M adopts a stable α-helical structure upon membrane binding, facilitated by a cation-π interaction between its phenylalanine side chain and the lipid headgroup. This interaction makes the membrane-bound state energetically favorable, facilitating membrane affinity and insertion. The bound peptide displayed asymmetric insertion depths, with the C-terminus penetrating deeper (approximately 9 Å) than the N-terminus (approximately 4.3 Å) relative to the lipid headgroups. Contrary to expectations, peptide dynamics was not hindered by membrane binding and exhibited rapid motions similar to cell-penetrating peptides. These dynamic interactions and peptide-lipid affinity appear to be crucial for membrane permeation. MD simulations indicated a thermodynamically stable transmembrane conformation of ATSP-7041M, reducing the energy barrier for translocation. Our study offers an in silico view of ATSP-7041M's translocation from the extracellular to the intracellular region, highlighting the significance of peptide-lipid interactions and dynamics in enabling peptide transit through membranes.
Subject(s)
Lipid Bilayers , Molecular Dynamics Simulation , Tumor Suppressor Protein p53 , Lipid Bilayers/chemistry , Lipid Bilayers/metabolism , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/metabolism , Nuclear Magnetic Resonance, Biomolecular , Magnetic Resonance SpectroscopyABSTRACT
Ganciclovir, a guanine analogue, is used intravenously (IV) first-line for the prophylaxis and treatment of cytomegalovirus (CMV) infection in solid organ transplant recipients. The pharmacokinetics (PK) of ganciclovir are highly variable, with myelosuppression occurring at high concentrations. Ganciclovir is primarily renally excreted as the parent compound, and clearance is significantly reduced in renal impairment. Acute kidney injury (AKI) is a common post-operative complication of cardiac transplantation, reducing the clearance of ganciclovir. In the intensive care unit (ICU), AKI is often managed by kidney replacement therapy (KRT). One form of KRT, prolonged intermittent kidney replacement therapy (PIKRT) is increasingly used for cost and flexibility advantages. Ganciclovir dosing recommendations are available for varying degrees of renal impairment and KRT, except for PIKRT. In this case of cardiac transplantation, complicated by anuric AKI, a ganciclovir dose of 2.0-2.5 mg/kg of adjusted body weight given after each PIKRT session was demonstrated to achieve PK targets.
ABSTRACT
BACKGROUND: Postinfectious Lyme arthritis (LA) is associated with dysregulated immunity and autoreactive T- and B-cell responses in joints. Here we explored the role of host genetic variation in this outcome. METHODS: The frequency of 253 702 single-nucleotide polymorphisms (SNPs) was determined in 147 patients with LA (87 with postinfectious LA and 60 with antibiotic-responsive LA), and for comparison in 90 patients with erythema migrans or the general population (n = 2504). Functional outcome of candidate SNPs was assessed by evaluating their impact on clinical outcome and on immune responses in blood and synovial fluid in patients with LA. RESULTS: Six SNPs associated with late cornified envelope (LCE3) genes were present at greater frequency in patients with postinfectious LA compared to those with antibiotic-responsive LA (70% vs 30%; odds ratio, 2; P < .01). These SNPs were associated with heightened levels of inflammatory Th17 cytokines in serum but lower levels of interleukin 27, a regulatory cytokine, implying that they may contribute to dysregulated Th17 immunity in blood. Moreover, in patients with postinfectious LA, the levels of these Th17 mediators correlated directly with autoantibody responses in synovial fluid, providing a possible link between LCE3 SNPs, maladaptive systemic Th17 immunity, and autoreactive responses in joints. CONCLUSIONS: Variation in the LCE3 locus, a known genetic risk factor in psoriasis and psoriatic arthritis, is associated with dysregulated systemic Th17 immunity and heightened autoantibody responses in joints. These findings underscore the importance of host genetic predisposition and systemic Th17 immunity in the pathogenesis of postinfectious (antibiotic-refractory) Lyme arthritis.
Subject(s)
Lyme Disease , Polymorphism, Single Nucleotide , Th17 Cells , Humans , Lyme Disease/genetics , Lyme Disease/immunology , Th17 Cells/immunology , Male , Female , Adult , Middle Aged , Synovial Fluid/immunology , Aged , Cytokines/genetics , Cytokines/metabolism , Arthritis, Infectious/genetics , Arthritis, Infectious/immunology , Young AdultABSTRACT
Abstract: Disease surveillance data was critical in supporting public health decisions throughout the coronavirus disease 2019 (COVID-19) pandemic. At the same time, the unprecedented circumstances of the pandemic revealed many shortcomings of surveillance systems for viral respiratory pathogens. Strengthening of surveillance systems was identified as a priority for the recently established Australian Centre for Disease Control, which represents a critical opportunity to review pre-pandemic and pandemic surveillance practices, and to decide on future priorities, during both pandemic and inter-pandemic periods. On 20 October 2022, we ran a workshop with experts from the academic and government sectors who had contributed to the COVID-19 response in Australia on 'The role of surveillance in epidemic response', at the University of New South Wales, Sydney, Australia. Following the workshop, we developed five recommendations to strengthen respiratory virus surveillance systems in Australia, which we present here. Our recommendations are not intended to be exhaustive. We instead chose to focus on data types that are highly valuable yet typically overlooked by surveillance planners. Three of the recommendations focus on data collection activities that support the monitoring and prediction of disease impact and the effectiveness of interventions (what to measure) and two focus on surveillance methods and capabilities (how to measure). Implementation of our recommendations would enable more robust, timely, and impactful epidemic analysis.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/epidemiology , Australia/epidemiology , Pandemics , Population Surveillance , Epidemiological Monitoring , Public Health , Public Health SurveillanceABSTRACT
BACKGROUND: Immunocompromised hosts (ICH) experience more breakthrough infections and worse clinical outcomes following infection with COVID-19 than immunocompetent people. Prophylactic monoclonal antibody therapies can be challenging to access, and escape variants emerge rapidly. Immunity conferred through vaccination remains a central prevention strategy for COVID-19. COVID-19 vaccines do not elicit optimal immunity in ICH but boosting, through additional doses of vaccine improves humoral and cellular immune responses. This trial aims to assess the immunogenicity and safety of different COVID-19 vaccine booster strategies against SARS-CoV-2 for ICH in Australia. METHODS: Bringing optimised COVID-19 vaccine schedules to immunocompromised populations (BOOST-IC) is an adaptive randomised trial of one or two additional doses of COVID-19 vaccines 3 months apart in people living with HIV, solid organ transplant (SOT) recipients, or those who have haematological malignancies (chronic lymphocytic leukaemia, non-Hodgkin lymphoma or multiple myeloma). Key eligibility criteria include having received 3 to 7 doses of Australian Therapeutic Goods Administration (TGA)-approved COVID-19 vaccines at least 3 months earlier, and having not received SARS-CoV-2-specific monoclonal antibodies in the 3 months prior to receiving the study vaccine. The primary outcome is the geometric mean concentration of anti-spike SARS-CoV-2 immunoglobulin G (IgG) 28 days after the final dose of the study vaccine. Key secondary outcomes include anti-spike SARS-CoV-2 IgG titres and the proportion of people seroconverting 6 and 12 months after study vaccines, local and systemic reactions in the 7 days after vaccination, adverse events of special interest, COVID-19 infection, mortality and quality of life. DISCUSSION: This study will enhance the understanding of COVID-19 vaccine responses in ICH, and enable the development of safe, and optimised vaccine schedules in people with HIV, SOT, or haematological malignancy. TRIAL REGISTRATION: ClinicalTrials.gov NCT05556720. Registered on 23rd August 2022.
Subject(s)
COVID-19 Vaccines , COVID-19 , Immunization Schedule , Immunocompromised Host , SARS-CoV-2 , Humans , COVID-19/prevention & control , COVID-19/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , SARS-CoV-2/immunology , Immunogenicity, Vaccine , Randomized Controlled Trials as Topic , Immunization, Secondary , Australia , Adult , Time FactorsABSTRACT
PURPOSE: To evaluate anatomic outcomes and surgeon response following the use of microserrated (Sharkskin, Alcon, Forth Worth, TX) internal limiting membrane (ILM) forceps compared with conventional (Grieshaber; Alcon) ILM forceps for peeling of the ILM. METHODS: Patients were prospectively assigned in a 1:1 randomized fashion to undergo ILM peeling using microserrated forceps or conventional forceps. Rates of retinal hemorrhages, deep retinal grasps, ILM regrasping, time to ILM removal, and surgeon questionnaire comparing the use of microserrated and conventional ILM forceps were analyzed. RESULTS: A total of 90 eyes of 90 patients were included in this study. The mean number of deep retinal grasps was higher in the conventional forceps group (1.51 ± 1.70 vs. 0.33 ± 0.56, respectively [P < 0.0001]). The mean number of failed ILM grasps was higher with conventional forceps (6.62 ± 3.51 vs. 5.18 ± 2.06 [P = 0.019]). Microserrated forceps provided more comfortability (lower number) in initiating the ILM flap (2.16 ± 0.85 vs. 1.56 ± 0.76, P < 0.001), comfortability in regrasping the ILM flap (2.51 ± 1.01 vs. 1.98 ± 0.89, P = 0.01), and comfortability in completing the ILM flap (2.42 ± 1.03 vs. 1.84 ± 1.02, P = 0.01). CONCLUSION: Surgeons utilizing the microserrated forceps experienced fewer deep retina grasps and fewer failed ILM grasps compared with conventional ILM forceps. The microserrated forceps was also a more favorable experience subjectively among the surgeons.
Subject(s)
Basement Membrane , Visual Acuity , Vitrectomy , Humans , Female , Male , Prospective Studies , Basement Membrane/surgery , Vitrectomy/instrumentation , Vitrectomy/methods , Aged , Middle Aged , Surgical Instruments , Epiretinal Membrane/surgery , Tomography, Optical Coherence , Equipment Design , Follow-Up Studies , Surgical FlapsABSTRACT
OBJECTIVE: To investigate the incidence and outcomes of retinal tear (RT) and retinal detachment (RD) after cataract extraction in patients with a history of previous phakic RT. DESIGN: Retrospective case series. SUBJECTS: Phakic eyes with RT that were successfully treated with laser photocoagulation or cryotherapy and subsequently underwent cataract surgery. METHOD: A retrospective review of phakic eyes treated for RTs between April 1, 2012 and May 31, 2023 was performed. Exclusions included prior vitreoretinal surgery before cataract removal and follow-up of less than 6 months post-cataract surgery. MAIN OUTCOME MEASURES: The incidence of RTs and RDs after cataract surgery, along with visual and anatomic outcomes. RESULTS: Of 12,109 phakic eyes treated for RTs, 1039 (8.6%) eyes underwent cataract surgery. After exclusions, 713 eyes of 660 patients were studied. The mean (standard deviation, SD) follow-up period post-cataract surgery was 34.8 (24.6) months with a median of 239 and 246 days to a new RT or RD development. The overall incidence for diagnosis of post-cataract surgery RT and RD was 7.3% (52/713) (2.9% and 4.3%, respectively), with a one-year incidence of 5.6% (2.2% and 3.4%, respectively). Multivariable regression analysis identified a higher risk of RT/RD among younger individuals (odds ratio [OR] 1.034; 95% confidence interval [CI] 1.004-1.065, P=0.028), males (OR 2.058; 95% CI 1.110-3.816, P=0.022), and those with shorter interval between laser treatment and cataract surgery (OR 1.001; 95% CI 1.001-1.001, P=0.011). Single surgery anatomic success for the RD repair was achieved in 25 eyes (80.6%) at 3 months, with a 100% final reattachment rate. The median final logMAR visual acuity was 0.10 (20/25) for RT, showing no significant change from post-cataract surgery, and 0.18 (20/30) for RD, a significant worsening from after cataract surgery. CONCLUSION: One year post-cataract surgery, the rate of diagnosed RT and RD in patients with previously treated RTs was relatively high, occurring in nearly 1 in 18 eyes. Higher risk was noted among younger individuals, males, and patients with a shorter interval between initial treatment for RT and cataract surgery. RD repair achieved good anatomical results, but vision declined.
ABSTRACT
Abstract: Annual seasonal influenza epidemics cause substantial disease and economic burden worldwide. During the coronavirus disease 2019 (COVID-19) pandemic in 2020 and 2021, influenza activity significantly declined. However, influenza resurged in Australia following the relaxation of non-pharmaceutical interventions, with increased influenza virus circulation in early 2022 coinciding with the SARS-CoV-2 Omicron BA.2 variant wave. Together with other respiratory virus diseases, these disease impacts on the Australian population and healthcare system have re-emphasised the importance of influenza vaccination and control. We aim to provide an overview of the current seasonal influenza vaccination program in Australia and summarise evidence and considerations underpinning potential future immunisation strategies. Influenza causes disproportionately higher morbidity and mortality in young children and older adults. Other populations at elevated risk from influenza include Aboriginal and Torres Strait Islander peoples, pregnant women, and people with certain underlying medical conditions. All Australians aged ≥ 6 months are recommended to receive influenza vaccine every year. The National Immunisation Program (NIP) provides free vaccine for eligible at-risk populations. While approximately 70% of older adults had received influenza vaccine in 2022, coverage in other age groups remains suboptimal. There are several key unmet needs and challenges, but also potential strategies for enhancing the influenza vaccination program in Australia. Improved monitoring and evaluation, including the use of relevant linked datasets for such purposes, is imperative to better understand variations in coverage and vaccination impact in specific populations. Adoption of evidence-based strategies, such as culturally appropriate resources that consider the characteristics of diverse Australian populations, may also help to achieve higher vaccine coverage rates. Additionally, greater vaccine uptake across the population could be facilitated by expanding the NIP-eligible population where cost-effective, and adopting the use of more effective and different types of vaccines when available.
Subject(s)
COVID-19 , Immunization Programs , Influenza Vaccines , Influenza, Human , Humans , Australia/epidemiology , COVID-19/prevention & control , COVID-19/epidemiology , Influenza Vaccines/administration & dosage , Influenza Vaccines/adverse effects , Influenza, Human/prevention & control , Influenza, Human/epidemiology , SARS-CoV-2/immunology , Vaccination/adverse effects , Adult , Female , Child , Aged , Adolescent , Child, Preschool , Infant , Middle Aged , Young Adult , Annual Reports as Topic , Pregnancy , MaleABSTRACT
OBJECTIVE: HLA-DR-expressing fibroblast-like synoviocytes (FLS) are a prominent cell type in synovial tissue in chronic inflammatory forms of arthritis. FLS-derived extracellular matrix (ECM) proteins, including fibronectin-1 (FN1), contain immunogenic CD4+ T cell epitopes in patients with postinfectious Lyme arthritis (LA). However, the role of FLS in presentation of these T cell epitopes remains uncertain. METHODS: Primary LA FLS and primary murine FLS stimulated with interferon gamma (IFNγ), Borrelia burgdorferi, and/or B burgdorferi peptidoglycan (PG) were assessed for properties associated with antigen presentation. HLA-DR-presented peptides from stimulated LA FLS were identified by immunopeptidomics analysis. OT-II T cells were co-cultured with stimulated murine FLS in the presence of cognate ovalbumin antigen to determine the potential of FLS to act as inducible antigen presenting cells (APCs). RESULTS: FLS expressed HLA-DR molecules within inflamed synovial tissue and tendons from patients with postinfectious LA in situ. Major histocompatibility complex (MHC) class II and co-stimulatory molecules were expressed by FLS following in vitro stimulation with IFNγ and B burgdorferi and presented both foreign and self-MHC-II peptides, including an immunogenic T cell epitope derived from Lyme autoantigen FN1. Stimulated FLS induced proliferation of naive OT-II CD4+ T cells that were dependent on OT-II antigen and CD40. Stimulation with B burgdorferi PG enhanced FLS-mediated T cell activation. CONCLUSION: MHC-II+ FLS are inducible APCs that can induce CD4+ T cell activation in an antigen- and CD40-dependent manner. Activated FLS can also present ECM-derived Lyme autoantigens, implicating FLS in amplifying tissue-localized autoimmunity in LA.
ABSTRACT
BACKGROUND: Daily airway clearance therapy (ACT) is a critical aspect of treatment in cystic fibrosis (CF), but poor adherence is a prominent concern. Identifying factors that might enhance or diminish adherence is a priority for treatment centers. Gratitude, a generalized tendency to notice and appreciate positive facets of experience, is a psychosocial resource that has commanded growing research interest. This longitudinal study examined whether gratitude at baseline was associated with ongoing or persistent ACT adherence over the course of a year. METHODS: Trait gratitude was evaluated at baseline using a validated measure, among adults receiving care at a regional CF treatment center. Self-reported adherence to ACT was assessed at baseline, 6 months, and 12 months using the Cystic Fibrosis Treatment Questionnaire. Average age of participants was 27.2 years, 45.5% were women, and 19.7% had severe disease. RESULTS: In multivariable logistic regression models that accounted for disease severity (Forced Expiratory Volume1% predicted) and other clinical and demographic variables, individuals with higher baseline gratitude were significantly more likely to demonstrate persistent adherence over the course of the year. Gratitude remained predictive after additionally adjusting for other well-known psychosocial resource variables (social support and emotional well-being). CONCLUSION: This is among the first demonstrations that gratitude is associated with persistent self-reported adherence to treatment over time. Findings suggest that gratitude may be important psychosocial resource for adults with CF, as they contend with complex, highly burdensome treatment regimens. Further research is warranted to examine these relationships and their impact on downstream health outcomes.
ABSTRACT
Oral squamous cell carcinoma (OSCC) biomarker studies rarely employ multi-omic biomarker strategies and pertinent clinicopathologic characteristics to predict mortality. In this study we determine for the first time a combined epigenetic, gene expression, and histology signature that differentiates between patients with different tobacco use history (heavy tobacco use with ≥10 pack years vs. no tobacco use). Using The Cancer Genome Atlas (TCGA) cohort (n = 257) and an internal cohort (n = 40), we identify 3 epigenetic markers (GPR15, GNG12, GDNF) and 13 expression markers (IGHA2, SCG5, RPL3L, NTRK1, CD96, BMP6, TFPI2, EFEMP2, RYR3, DMTN, GPD2, BAALC, and FMO3), which are dysregulated in OSCC patients who were never smokers vs. those who have a ≥ 10 pack year history. While mortality risk prediction based on smoking status and clinicopathologic covariates alone is inaccurate (c-statistic = 0.57), the combined epigenetic/expression and histologic signature has a c-statistic = 0.9409 in predicting 5-year mortality in OSCC patients.
ABSTRACT
Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC.
Subject(s)
Drug Resistance, Neoplasm , Humans , Male , Animals , Mice , Drug Resistance, Neoplasm/genetics , Cell Line, Tumor , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/drug therapy , Cell Proliferation , Gene Expression Regulation, Neoplastic , Cell Lineage/genetics , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , Xenograft Model Antitumor Assays , Cell Plasticity/genetics , Receptors, Cell Surface/metabolism , Receptors, Cell Surface/genetics , Prognosis , Membrane Glycoproteins , Intracellular Signaling Peptides and ProteinsABSTRACT
BACKGROUND: Hospital-acquired pneumonia (HAP) also known as non-ventilator associated pneumonia, is one of the most common infections acquired in hospitalised patients. Improving oral hygiene appears to reduce the incidence of HAP. This study aimed to describe current practices, barriers and facilitators, knowledge and educational preferences of registered nurses performing oral health care in the Australian hospital setting, with a focus on the prevention of HAP. We present this as a short research report. METHODS: We undertook a cross sectional online anonymous survey of Australian registered nurses. Participants were recruited via electronic distribution through existing professional networks and social media. The survey used was modified from an existing survey on oral care practice. RESULTS: The survey was completed by 179 participants. Hand hygiene was considered a very important strategy to prevent pneumonia (n = 90, 58%), while 45% (n = 71) felt that oral care was very important. The most highly reported barriers for providing oral care included: an uncooperative patient; inadequate staffing; and a lack of oral hygiene requisite. Patients' reminders, prompts and the provision of toothbrushes were common ways believed to help facilitate improvements in oral care. CONCLUSION: Findings from this survey will be used in conjunction with consumer feedback, to help inform a planned multi-centre randomised trial, the Hospital Acquired Pneumonia PrEveNtion (HAPPEN) study, aimed at reducing the incidence of HAP. Findings may also be useful for informing studies and quality improvement initiatives aimed at improving oral care to reduce the incidence of HAP.
ABSTRACT
The anterolateral system (ALS) is a major ascending pathway from the spinal cord that projects to multiple brain areas and underlies the perception of pain, itch, and skin temperature. Despite its importance, our understanding of this system has been hampered by the considerable functional and molecular diversity of its constituent cells. Here, we use fluorescence-activated cell sorting to isolate ALS neurons belonging to the Phox2a-lineage for single-nucleus RNA sequencing. We reveal five distinct clusters of ALS neurons (ALS1-5) and document their laminar distribution in the spinal cord using in situ hybridization. We identify three clusters of neurons located predominantly in laminae I-III of the dorsal horn (ALS1-3) and two clusters with cell bodies located in deeper laminae (ALS4 and ALS5). Our findings reveal the transcriptional logic that underlies ALS neuronal diversity in the adult mouse and uncover the molecular identity of two previously identified classes of projection neurons. We also show that these molecular signatures can be used to target groups of ALS neurons using retrograde viral tracing. Overall, our findings provide a valuable resource for studying somatosensory biology and targeting subclasses of ALS neurons.
Subject(s)
Homeodomain Proteins , Animals , Mice , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Spinal Cord/cytology , Spinal Cord/metabolism , Neurons/metabolism , High-Throughput Nucleotide Sequencing , Male , Cell Nucleus/metabolism , Cell Nucleus/genetics , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.
ABSTRACT
Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 is highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression is associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibit neural lineage pathways, suppressing NEPC cell proliferation, PDX tumor organoid viability, and xenograft tumor growth. Mechanistically, the chaperone protein HSP70 regulates PLXND1 protein stability through degradation, and inhibition of HSP70 decreases PLXND1 expression and NEPC organoid growth. In summary, our findings suggest that PLXND1 could be a new therapeutic target and molecular indicator for NEPC.