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1.
Vet Parasitol ; 331: 110252, 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-39079236

ABSTRACT

The eastern paralysis tick, Ixodes holocyclus, is a tick of much veterinary importance in Australia. Each year, thousands of dogs and cats present to veterinary clinics and hospitals with signs of tick paralysis. In a previous paper, we constructed two models to explain prevalence and temporal distributions of tick paralysis cases presenting to emergency veterinary hospitals in South East Queensland (2009-2020) and the Northern Beaches of Sydney (1999-2017). The first model accounted for the intensity of the clinical burden of tick paralysis based on the prevalence of cases of tick paralysis in the tick paralysis season whereas the second model accounted for the start of the tick paralysis season. In the present paper, we test our models further, with much additional data from 2021 to 2023 (South East Queensland) and from 2018 to 2023 (Northern Beaches of Sydney). During the defined tick paralysis season in these locations, 10.3 % (3207 of 31,217) of veterinary-consultations were for tick paralysis. On average, predictions for the prevalence of cases of tick paralysis were 1.3 % (0.013) away from the actual prevalence whereas predictions for the start of the tick paralysis season were 1.7 weeks away from the actual start of the season. The prediction of the prevalence of tick paralysis cases was most accurate for Brisbane and least accurate for the Northern Beaches of Sydney whereas, curiously, the prediction for the start of the tick paralysis season was most accurate for the Northern Beaches of Sydney and least accurate for Brisbane. We re-fitted the models with the new data. We predict that about 10 % (Sunshine Coast), 5 % (Brisbane), 7 % (Gold Coast) and 12 % (Northern Beaches of Sydney) of veterinary-consultations in the tick paralysis season of 2024 will be cases of tick paralysis, resulting in a tick paralysis clinical burden intensity of similar magnitude to previous years. Such predictions allow for timely public education campaigns around the importance of prevention and appropriate resource planning for veterinary clinics.

3.
Infect Dis Ther ; 13(4): 891-906, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38570443

ABSTRACT

INTRODUCTION: Dolutegravir/lamivudine (DTG/3TC) and dolutegravir/rilpivirine (DTG/RPV) are fixed-dose, complete, single-tablet, two-drug regimens (2DRs) indicated for HIV-1. DTG/3TC is approved for antiretroviral therapy (ART)-naive people with HIV-1 and virologically suppressed individuals to replace current ART; DTG/RPV is indicated for virologically suppressed individuals as a switch option. Virologic efficacy and effectiveness of these DTG-based 2DRs have been demonstrated in phase 3 clinical trials and real-world cohorts, primarily from Europe. This study characterized real-world use of DTG-based 2DRs for HIV-1 treatment in the USA. METHODS: TANDEM was a retrospective medical chart review across 24 US sites. Individuals aged ≥ 18 years who initiated DTG/3TC or DTG/RPV before September 30, 2020, with ≥ 6 months of follow-up were included. One cohort included ART-naive people who initiated DTG/3TC (n = 126), and two other cohorts included virologically suppressed (HIV-1 RNA < 50 copies/mL) people on stable ART regimens for ≥ 3 months before switch to either DTG/3TC (n = 192) or DTG/RPV (n = 151). Clinical characteristics, treatment history, and outcomes are described. RESULTS: Virologically suppressed individuals were older than those who were ART-naive, and the ART-naive cohort had higher proportions of individuals assigned male at birth and of Hispanic ethnicity. The most common healthcare provider-reported reason for choosing a DTG-based 2DR was avoidance of long-term toxicities (25-33% across cohorts), followed by simplification/streamlining of treatment. Among ART-naive people on DTG/3TC, 94% achieved virologic suppression after initiation, and 83% maintained suppression at last follow-up; discontinuation rate was < 1%. Among cohorts who switched to DTG-based 2DRs, 96% maintained virologic suppression on DTG/3TC and 93% on DTG/RPV; 2% on DTG/3TC and 3% on DTG/RPV discontinued. CONCLUSION: Motivation for selecting DTG-based 2DRs was primarily driven by a desire to avoid or manage toxicities and simplify treatment. Results demonstrate that DTG/3TC and DTG/RPV are effective in real-world settings, with few discontinuations, reflecting data from clinical trials.

4.
Infect Dis Ther ; 13(4): 875-889, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38570444

ABSTRACT

INTRODUCTION: Dolutegravir/lamivudine (DTG/3TC) was first approved by the US Food and Drug Administration in 2019 for the treatment of antiretroviral therapy (ART)-naive people with HIV-1 based on results from the pivotal GEMINI-1/GEMINI-2 trials. Around that time, immediate initiation of treatment upon diagnosis was recommended in the US Department of Health and Human Services guidelines. Here we report results from 126 treatment-naive people with HIV-1 who initiated DTG/3TC as part of a test-and-treat strategy (n = 61) or with high baseline viral loads (HIV-1 RNA ≥ 100,000 copies/ml; n = 16) from the TANDEM study. METHODS: TANDEM was a US-based, retrospective chart review study that included a cohort of 126 individuals aged ≥ 18 years with no prior history of ART who initiated DTG/3TC before September 30, 2020, and had ≥ 6 months of follow-up. Test-and-treat was defined as ART initiation shortly after diagnosis without available viral load, CD4 + cell count, or HIV-1 resistance data. Outcomes included virologic suppression (HIV-1 RNA < 50 copies/ml; overall and by baseline viral load) and discontinuations. Analyses were descriptive. RESULTS: Among 61 individuals who initiated DTG/3TC in a test-and-treat setting (median [interquartile range (IQR)] treatment duration, 1.3 [0.9-1.7] years), 57 (93%) achieved virologic suppression, and 51 (84%) remained suppressed; 1 (< 1%) individual discontinued DTG/3TC due to persistent low-level viremia. The most common healthcare provider (HCP)-reported reason for initiating DTG/3TC was avoidance of long-term toxicities among individuals in the test-and-treat subgroup. Of 16 treatment-naive individuals with high baseline viral loads (median [IQR] treatment duration, 100,000-250,000 copies/ml: 1.2 [0.8-1.8] years; > 250,000 copies/ml: 1.0 [0.7-1.1] years), 14 (88%) achieved virologic suppression, 13 (81%) remained suppressed, and none discontinued DTG/3TC. Patient preference was the most common HCP-reported reason for initiating DTG/3TC in this subgroup. CONCLUSIONS: Results demonstrate real-world effectiveness of DTG/3TC, with few discontinuations, in people with HIV-1 in test-and-treat settings or with high baseline viral loads.

5.
Curr Med Res Opin ; 39(12): 1717-1728, 2023 12.
Article in English | MEDLINE | ID: mdl-37994434

ABSTRACT

OBJECTIVE: Treatment options for adults with chronic cough (CC) are limited. This study reports on the health status and experiences of patients with recent healthcare evaluation for CC. METHODS: This prospective, UK, cross-sectional study surveyed adults with a CC evaluation within the previous 12 months. All were never smokers (or ex-smokers for ≥12 months). Subjects completed five validated patient-reported outcome measures: cough visual analogue scale (VAS), EuroQoL 5 dimension, 5 level (EQ-5D-5L), EQ-5D VAS, Leicester Cough Questionnaire (LCQ), and Work Productivity and Activity Impairment (WPAI) questionnaire. RESULTS: A total of 101 participants were recruited: 71% were female, mean age was 54.9 ± 15.2 years. Median (IQR) CC duration was 36 (11, 120) months. Mean self-reported CC severity (Cough-VAS) was 51.3 ± 22.9 over the previous 2 weeks and 62.9 ± 23.7 on the worst day of coughing. EQ-5D values were lower for CC patients than population norms. Subanalyses revealed that EQ-5D and LCQ scores were significantly impacted by CC duration and the number of healthcare providers (HCPs) visited. WPAI analysis showed a 27.6% work time impairment because of participants' CC. The number of HCP attendances ranged from 1 to 10 (3.3 ± 2.8) before diagnosis was confirmed. Treatment was being prescribed to 87% of participants and comprised mainly steroids (nasal [19%] and inhaled [25%]), beta agonists (24%), and proton pump inhibitors (21%); 44% of patients were dissatisfied with treatment efficacy. CONCLUSION: Real-world data from a nationally representative UK population show significant unmet needs associated with CC, including multiple healthcare visits and limited treatment effectiveness, resulting in inadequate cough control and impaired health status.


Subject(s)
Quality of Life , Adult , Humans , Female , Middle Aged , Aged , Male , Cross-Sectional Studies , Prospective Studies , Health Status , Cough/diagnosis , Cough/epidemiology , Surveys and Questionnaires , United Kingdom/epidemiology
6.
Science ; 381(6664): 1324-1330, 2023 09 22.
Article in English | MEDLINE | ID: mdl-37733857

ABSTRACT

Pregnancy confers partner-specific protection against complications in future pregnancy that parallel persistence of fetal microchimeric cells (FMcs) in mothers after parturition. We show that preexisting FMcs become displaced by new FMcs during pregnancy and that FMc tonic stimulation is essential for expansion of protective fetal-specific forkhead box P3 (FOXP3)-positive regulatory T cells (Treg cells). Maternal microchimeric cells and accumulation of Treg cells with noninherited maternal antigen (NIMA) specificity are similarly overturned in daughters after pregnancy, highlighting a fixed microchimeric cell niche. Whereas NIMA-specific tolerance is functionally erased by pregnancy, partner-specific resiliency against pregnancy complications persists in mothers despite paternity changes in intervening pregnancy. Persistent fetal tolerance reflects FOXP3 expression plasticity, which allows mothers to more durably remember their babies, whereas daughters forget their mothers with new pregnancy-imprinted immunological memories.


Subject(s)
Chimerism , Fetus , Immune Tolerance , Immunologic Memory , Maternal-Fetal Exchange , Pregnancy , Animals , Female , Mice , Pregnancy/immunology , Antigens/immunology , Cell Plasticity , Fetus/cytology , Fetus/immunology , Forkhead Transcription Factors/immunology , Maternal-Fetal Exchange/immunology , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/immunology
8.
J Asthma ; 58(8): 1094-1101, 2021 08.
Article in English | MEDLINE | ID: mdl-32469667

ABSTRACT

BACKGROUND: One of the most commonly observed asthma treatment patterns is the underuse of inhaled corticosteroid (ICS) maintenance therapy when patients are not experiencing symptoms, and the predominant use of short-acting ß2-agonists (SABAs) when patients are experiencing symptoms. This multinational study investigated the current beliefs and behaviors related to reliance on reliever inhalers among asthma patients, and the reasons why patients may not adhere to their recommended maintenance controller treatment. METHODS: This was a qualitative research study, in which 80 patients with asthma who were receiving reliever therapy (i.e. SABAs) were interviewed, in-depth, for 60 min. The interview questions focused on the patients' experience of living with asthma and their inhaled treatment regimens. RESULTS: The key insights identified in the interviews were (a) patients had a strong emotional attachment to SABA relievers driven by their efficacy and success in quickly alleviating asthma symptoms, with the reliever also becoming an emotional support; (b) patients typically did not understand that the frequent use of SABAs indicates poor asthma control; (c) patients had a misperception of ICS, which could lead to a delay in escalation and poor adherence; and (d) severe exacerbations improve adherence to ICS, but only temporarily in many cases. CONCLUSION: This study confirmed the poor level of control patients have over their asthma, and how this affects their lifestyle and daily activities. Our results also confirmed that the patients' perception of both the disease and treatment plays a key role in SABA reliance and ICS underuse.


Subject(s)
Adrenergic beta-2 Receptor Agonists/therapeutic use , Asthma/drug therapy , Administration, Inhalation , Adolescent , Adrenal Cortex Hormones/administration & dosage , Adult , Aged , Emotions , Female , Humans , Male , Middle Aged , Qualitative Research , Young Adult
9.
Nature ; 578(7794): E20, 2020 02.
Article in English | MEDLINE | ID: mdl-31959987

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

10.
Nature ; 575(7781): 75-86, 2019 11.
Article in English | MEDLINE | ID: mdl-31695206

ABSTRACT

Rapid growth in the market for electric vehicles is imperative, to meet global targets for reducing greenhouse gas emissions, to improve air quality in urban centres and to meet the needs of consumers, with whom electric vehicles are increasingly popular. However, growing numbers of electric vehicles present a serious waste-management challenge for recyclers at end-of-life. Nevertheless, spent batteries may also present an opportunity as manufacturers require access to strategic elements and critical materials for key components in electric-vehicle manufacture: recycled lithium-ion batteries from electric vehicles could provide a valuable secondary source of materials. Here we outline and evaluate the current range of approaches to electric-vehicle lithium-ion battery recycling and re-use, and highlight areas for future progress.

11.
Infect Genet Evol ; 58: 50-55, 2018 03.
Article in English | MEDLINE | ID: mdl-29253672

ABSTRACT

Tracing the temporal dynamics of pathogens is crucial for developing strategies to detect and limit disease emergence. Canine parvovirus (CPV-2) is an enteric virus causing morbidity and mortality in dogs around the globe. Previous work in Australia reported that the majority of cases were associated with the CPV-2a subtype, an unexpected finding since CPV-2a was rapidly replaced by another subtype (CPV-2b) in many countries. Using a nine-year dataset of CPV-2 infections from 396 dogs sampled across Australia, we assessed the population dynamics and molecular epidemiology of circulating CPV-2 subtypes. Bayesian phylogenetic Skygrid models and logistic regressions were used to trace the temporal dynamics of CPV-2 infections in dogs sampled from 2007 to 2016. Phylogenetic models indicated that CPV-2a likely emerged in Australia between 1973 and 1988, while CPV-2b likely emerged between 1985 and 1998. Sequences from both subtypes were found in dogs across continental Australia and Tasmania, with no apparent effect of climate variability on subtype occurrence. Both variant subtypes exhibited a classical disease emergence pattern of relatively high rates of evolution during early emergence followed by subsequent decreases in evolutionary rates over time. However, the CPV-2b subtype maintained higher mutation rates than CPV-2a and continued to expand, resulting in an increase in the probability that dogs will carry this subtype over time. Ongoing monitoring programs that provide molecular epidemiology surveillance will be necessary to detect emergence of new variants and make informed recommendations to develop reliable detection and vaccine methods.


Subject(s)
Dog Diseases/epidemiology , Dog Diseases/virology , Genotype , Parvoviridae Infections/veterinary , Parvovirus, Canine/genetics , Animals , Australia/epidemiology , Communicable Diseases, Emerging/epidemiology , Communicable Diseases, Emerging/virology , DNA, Viral , Dogs , Geography , Molecular Epidemiology , Phylogeny , Public Health Surveillance , Sequence Analysis, DNA , Spatio-Temporal Analysis
12.
J Biomol Screen ; 14(1): 66-76, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19171922

ABSTRACT

The use of large-scale compound screening has become a key component of drug discovery projects in both the pharmaceutical and the biotechnological industries. More recently, these activities have also been embraced by the academic community as a major tool for chemical genomic activities. High-throughput screening (HTS) activities constitute a major step in the initial drug discovery efforts and involve the use of large quantities of biological reagents, hundreds of thousands to millions of compounds, and the utilization of expensive equipment. All these factors make it very important to evaluate in advance of the HTS campaign any potential issues related to reproducibility of the experimentation and the quality of the results obtained at the end of these very costly activities. In this article, the authors describe how GlaxoSmithKline (GSK) has addressed the need of a true validation of the HTS process before embarking in full HTS campaigns. They present 2 different aspects of the so-called validation process: (1) optimization of the HTS workflow and its validation as a quality process and (2) the statistical evaluation of the HTS, focusing on the reproducibility of results and the ability to distinguish active from nonactive compounds in a vast collection of samples. The authors describe a variety of reproducibility indexes that are either innovative or have been adapted from generic medical diagnostic screening strategies. In addition, they exemplify how these validation tools have been implemented in a number of case studies at GSK.


Subject(s)
Drug Evaluation, Preclinical/methods , Algorithms , Reproducibility of Results
13.
J Med Chem ; 51(24): 7898-914, 2008 Dec 25.
Article in English | MEDLINE | ID: mdl-19035792

ABSTRACT

More than 500 compounds chosen to represent kinase inhibitor space have been screened against a panel of over 200 protein kinases. Significant results include the identification of hits against new kinases including PIM1 and MPSK1, and the expansion of the inhibition profiles of several literature compounds. A detailed analysis of the data through the use of affinity fingerprints has produced findings with implications for biological target selection, the choice of tool compounds for target validation, and lead discovery and optimization. In a detailed examination of the tyrosine kinases, interesting relationships have been found between targets and compounds. Taken together, these results show how broad cross-profiling can provide important insights to assist kinase drug discovery.


Subject(s)
Chemistry, Pharmaceutical/methods , Drug Delivery Systems , Phosphotransferases/chemistry , Crystallography, X-Ray , Drug Design , Drug Discovery , Humans , Kinetics , Molecular Weight , Phosphotransferases/metabolism , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinases/chemistry , Protein Serine-Threonine Kinases/chemistry , Protein-Tyrosine Kinases/chemistry , Proto-Oncogene Proteins c-pim-1/chemistry , Transcription Factors/chemistry
14.
J Chem Inf Model ; 48(8): 1543-57, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18630899

ABSTRACT

A new machine learning method is presented for extracting interpretable structure-activity relationships from screening data. The method is based on an evolutionary algorithm and reduced graphs and aims to evolve a reduced graph query (subgraph) that is present within the active compounds and absent from the inactives. The reduced graph representation enables heterogeneous compounds, such as those found in high-throughput screening data, to be captured in a single representation with the resulting query encoding structure-activity information in a form that is readily interpretable by a chemist. The application of the method is illustrated using data sets extracted from the well-known MDDR data set and GSK in-house screening data. Queries are evolved that are consistent with the known SARs, and they are also shown to be robust when applied to independent sets that were not used in training.


Subject(s)
Combinatorial Chemistry Techniques/methods , Algorithms , Chromosomes/genetics , Humans , Phenotype , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists , Structure-Activity Relationship
15.
J Chem Inf Model ; 48(8): 1558-70, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18637673

ABSTRACT

A multiobjective evolutionary algorithm (MOEA) is described for evolving multiple structure-activity relationships (SARs). The SARs are encoded in easy-to-interpret reduced graph queries which describe features that are preferentially present in active compounds compared to inactives. The MOEA addresses a limitation associated with many machine learning methods; that is, the inherent tradeoff that exists in recall and precision which is usually handled by combining the two objectives into a single measure with a consequent loss of control. By simultaneously optimizing recall and precision, the MOEA generates a family of SARs that lie on the precision-recall (PR) curve. The user is then able to select a query with an appropriate balance in the two objectives: for example, a low recall-high precision query may be preferred when establishing the SAR, whereas a high recall-low precision query may be more appropriate in a virtual screening context. Each query on the PR curve aims at capturing the structure-activity information into a single representation, and each can be considered as an alternative (equally valid) solution. We then investigate combining individual queries into teams with the aim of capturing multiple SARs that may exist in a data set, for example, as is commonly seen in high-throughput screening data sets. Team formation is carried out iteratively as a postprocessing step following the evolution of the individual queries. The inclusion of uniqueness as a third objective within the MOEA provides an effective way of ensuring the queries are complementary in the active compounds they describe. Substantial improvements in both recall and precision are seen for some data sets. Furthermore, the resulting queries provide more detailed structure-activity information than is present in a single query.


Subject(s)
Models, Biological , Algorithms , Humans , Molecular Structure , Receptors, Serotonin, 5-HT1/metabolism , Serotonin 5-HT1 Receptor Agonists , Structure-Activity Relationship
16.
Drug Discov Today ; 11(15-16): 694-9, 2006 Aug.
Article in English | MEDLINE | ID: mdl-16846796

ABSTRACT

Data mining is a fast-growing field that is finding application across a wide range of industries. HTS is a crucial part of the drug discovery process at most large pharmaceutical companies. Accurate analysis of HTS data is, therefore, vital to drug discovery. Given the large quantity of data generated during an HTS, and the importance of analyzing those data effectively, it is unsurprising that data-mining techniques are now increasingly applied to HTS data analysis. Taking a broad view of both the HTS process and the data-mining process, we review recent literature that describes the application of data-mining techniques to HTS data.


Subject(s)
Data Collection/methods , Drug Design , Drug Industry/methods , Animals , Drug Evaluation, Preclinical/methods , Humans , Information Storage and Retrieval/methods , Reproducibility of Results
17.
J Chem Inf Model ; 46(2): 577-86, 2006.
Article in English | MEDLINE | ID: mdl-16562986

ABSTRACT

Reduced graph representations of chemical structures have been shown to be effective in similarity searching applications where they offer comparable performance to other 2D descriptors in terms of recall experiments. They have also been shown to complement existing descriptors and to offer potential to scaffold hop from one chemical series to another. Various methods have been developed for quantifying the similarity between reduced graphs including fingerprint approaches, graph matching, and an edit distance method. The edit distance approach quantifies the degree of similarity of two reduced graphs based on the number and type of operations required to convert one graph to the other. An attractive feature of the edit distance method is the ability to assign different weights to different operations. For example, the mutation of an aromatic ring node to an acyclic node may be assigned a higher weight than the mutation of an aromatic ring to an aliphatic ring node. In this paper, we describe a genetic algorithm (GA) for training the weights of the different edit distance operations. The method is applied to specific activity classes extracted from the MDDR database to derive activity-class specific weights. The GA-derived weights give substantially improved results in recall experiments as compared to using weights assigned on intuition. Furthermore, such activity specific weights may provide useful structure--activity information for subsequent design efforts. In a virtual screening setting when few active compounds are known, it may be more useful to have weights that perform well across a variety of different activity classes. Thus, the GA is also trained on multiple activity classes simultaneously to derive a generalized set of weights. These more generally applicable weights also represent a substantial improvement on previous work.


Subject(s)
Algorithms , Artificial Intelligence , Computer Graphics , Models, Theoretical , Pharmaceutical Preparations/chemistry , Structure-Activity Relationship , Enzyme Inhibitors/chemistry
18.
J Med Chem ; 46(15): 3257-74, 2003 Jul 17.
Article in English | MEDLINE | ID: mdl-12852756

ABSTRACT

This paper describes the development of a drug rings database and Web-based search tools. The database contains ring structures from both corporate and commercial databases, along with characteristic descriptors including frequency of occurrence as an indicator of synthetic accessibility and calculated property and geometric parameters. Analysis of the rings in several major databases is described, with illustrations of applications of the database in lead discovery programs where bioisosteres and geometric isosteres are sought.


Subject(s)
Databases, Factual , Heterocyclic Compounds/chemistry , Internet , Pharmaceutical Preparations/chemistry , Drug Design , Endothelins/antagonists & inhibitors , Indoles/chemistry
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