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PURPOSE: In April 2020, the UK Government implemented NHS Test and Trace to provide SARS-CoV-2 quantitative reverse transcription polymerase chain reaction (qRT-PCR) testing for the public, with nose-and-throat swabbing for samples performed by trained staff. Self-swabbing (SS) would allow rapid scale-up of testing capacity and access. Six studies were undertaken to determine whether SS was as effective for detecting SARS-CoV-2 as swabbing performed by trained staff. METHODS: Six prospective studies were conducted between April-October 2020, using six swab/media combinations. Differences between assisted swabbing (AS) and SS were evaluated for concordance, positivity, sensitivity, cycle threshold (Ct) values and void rates. Statistical analysis was performed using 95% confidence intervals (CIs), paired t-tests and model-based methods. RESULTS: Overall, 3,253 individuals were recruited (median age 37 years, 49% female), with 2,933 having valid paired qRT-PCR results. Pooled concordance rate was 98% (95% CI: 96%, 99%). Positivity rate differences for SS (8.1%) and AS (8.4%) and differences in pooled sensitivities between SS (86%; 95% CI: 78%, 92%) and AS (91%; 95% CI: 78%, 96%) were nonsignificant. Both types of swabbing led to pooled void rates below 2% and strongly correlated Ct values. Age, sex and previous swabbing experience did not have a significant impact on concordance or sensitivity. CONCLUSION: The UK adopted a policy to promote self-testing for SARS-CoV-2 based on data demonstrating equivalence of SS versus AS. Positive outcomes with SS are likely generalisable to testing for other respiratory pathogens, and we consider self-sampling and self-testing essential for future pandemic preparedness.
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COVID-19 , SARS-CoV-2 , Manejo de Espécimes , Adulto , Feminino , Humanos , Masculino , COVID-19/diagnóstico , COVID-19/virologia , COVID-19/epidemiologia , Teste de Ácido Nucleico para COVID-19/métodos , Teste para COVID-19/métodos , Nariz/virologia , Faringe/virologia , Estudos Prospectivos , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Sensibilidade e Especificidade , Manejo de Espécimes/métodos , Reino UnidoRESUMO
AIMS: The number of older people with diabetes requiring care from district nursing teams is increasing. The role of district nursing teams in diabetes management has expanded to involve diagnosis, treatment and medication administration. As the complexity of caseloads increases, the current model is likely unsustainable. This study aims to understand the current diabetes workload of district nursing teams. METHODS: An online survey was distributed via social media and key stakeholder networks to district nursing teams. Survey items were designed by the researchers prior to pilot testing with potential participants. Descriptive statistical and qualitative analyses were conducted. Data are median ± IQR. RESULTS: 159 district nursing teams completed the survey. The median caseload per team was 300 (IQR 176-407) patients including 21 with diabetes (IQR 14-40; 8.7% (4-20%)). 1.09 home visits per day per person with diabetes lasting 13.8 minutes (excluding travel time) were needed, with most requiring insulin administration. 96% of nursing teams undertake multiple daily visits for some patients. 91% reported workloads relating to diabetes management had increased over the last 2 years; 76% stated current diabetes workloads were unsustainable. More insulin usage, more referrals and a lack of ability or willingness to self-administer insulin has increased the diabetes workload. Possible solutions include better collaboration between healthcare professionals, simplification of insulin administration and glucose monitoring, better training and upskilling of healthcare assistants and promotion of self-efficacy. CONCLUSIONS: Diabetes management forms an increasing component of district nursing workload and is likely to be unsustainable unless new models are found.
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The Cancer Programme of the 100,000 Genomes Project was an initiative to provide whole-genome sequencing (WGS) for patients with cancer, evaluating opportunities for precision cancer care within the UK National Healthcare System (NHS). Genomics England, alongside NHS England, analyzed WGS data from 13,880 solid tumors spanning 33 cancer types, integrating genomic data with real-world treatment and outcome data, within a secure Research Environment. Incidence of somatic mutations in genes recommended for standard-of-care testing varied across cancer types. For instance, in glioblastoma multiforme, small variants were present in 94% of cases and copy number aberrations in at least one gene in 58% of cases, while sarcoma demonstrated the highest occurrence of actionable structural variants (13%). Homologous recombination deficiency was identified in 40% of high-grade serous ovarian cancer cases with 30% linked to pathogenic germline variants, highlighting the value of combined somatic and germline analysis. The linkage of WGS and longitudinal life course clinical data allowed the assessment of treatment outcomes for patients stratified according to pangenomic markers. Our findings demonstrate the utility of linking genomic and real-world clinical data to enable survival analysis to identify cancer genes that affect prognosis and advance our understanding of how cancer genomics impacts patient outcomes.
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Glioblastoma , Medicina de Precisão , Humanos , Genômica , Oncogenes , Mutação em Linhagem Germinativa/genéticaAssuntos
Epilepsia , Espasmos Infantis , Humanos , Lactente , Epilepsia/diagnóstico , Epilepsia/genética , MutaçãoRESUMO
The technical development of high-throughput sequencing technologies and the parallel development of targeted therapies in the last decade have enabled a transition from traditional medicine to personalized treatment and care. In this way, by using comprehensive genomic testing, more effective treatments with fewer side effects are provided to each patient-that is, precision or personalized medicine (PM). In several European countries-such as in England, France, Denmark, and Spain-the governments have adopted national strategies and taken "top-down" decisions to invest in national infrastructure for PM. In other countries-such as Sweden, Germany, and Italy with regionally organized healthcare systems-the profession has instead taken "bottom-up" initiatives to build competence networks and infrastructure to enable equal access to PM. In this review, we summarize key learnings at the European level on the implementation process to establish sustainable governance and organization for PM at the regional, national, and EU/international levels. We also discuss critical ethical and legal aspects of implementing PM, and the importance of access to real-world data and performing clinical trials for evidence generation, as well as the need for improved reimbursement models, increased cross-disciplinary education and patient involvement. In summary, PM represents a paradigm shift, and modernization of healthcare and all relevant stakeholders-that is, healthcare, academia, policymakers, industry, and patients-must be involved in this system transformation to create a sustainable, non-siloed ecosystem for precision healthcare that benefits our patients and society at large.
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Ecossistema , Medicina de Precisão , Humanos , Atenção à Saúde , Europa (Continente) , AlemanhaRESUMO
Molecular diagnostics is a cornerstone of modern precision medicine, broadly understood as tailoring an individual's treatment, follow-up, and care based on molecular data. In rare diseases (RDs), molecular diagnoses reveal valuable information about the cause of symptoms, disease progression, familial risk, and in certain cases, unlock access to targeted therapies. Due to decreasing DNA sequencing costs, genome sequencing (GS) is emerging as the primary method for precision diagnostics in RDs. Several ongoing European initiatives for precision medicine have chosen GS as their method of choice. Recent research supports the role for GS as first-line genetic investigation in individuals with suspected RD, due to its improved diagnostic yield compared to other methods. Moreover, GS can detect a broad range of genetic aberrations including those in noncoding regions, producing comprehensive data that can be periodically reanalyzed for years to come when further evidence emerges. Indeed, targeted drug development and repurposing of medicines can be accelerated as more individuals with RDs receive a molecular diagnosis. Multidisciplinary teams in which clinical specialists collaborate with geneticists, genomics education of professionals and the public, and dialogue with patient advocacy groups are essential elements for the integration of precision medicine into clinical practice worldwide. It is also paramount that large research projects share genetic data and leverage novel technologies to fully diagnose individuals with RDs. In conclusion, GS increases diagnostic yields and is a crucial step toward precision medicine for RDs. Its clinical implementation will enable better patient management, unlock targeted therapies, and guide the development of innovative treatments.
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Medicina de Precisão , Doenças Raras , Humanos , Medicina de Precisão/métodos , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/terapia , Genômica/métodos , Análise de Sequência de DNA , Progressão da DoençaRESUMO
BACKGROUND: Infectious illness is the biggest cause of death in children due to a physical illness, particularly in children under five years. If mortality is to be reduced for this group of children, it is important to understand factors affecting their pathways to hospital. The aim of this study was to retrospectively identify organisational and environmental factors, and individual child, family, and professional factors affecting timing of admission to hospital for children under five years of age with a serious infectious illness (SII). METHODS: An explanatory modified grounded theory design was used in collaboration with parents. Two stages of data collection were conducted: Stage 1, interviews with 22 parents whose child had recently been hospitalised with a SII and 14 health professionals (HPs) involved in their pre-admission trajectories; Stage 2, focus groups with 18 parents and 16 HPs with past experience of SII in young children. Constant comparative analysis generated the explanatory theory. RESULTS: The core category was 'navigating uncertain illness trajectories for young children with serious infectious illness'. Uncertainty was prevalent throughout the parents' and HPs' stories about their experiences of navigating social rules and overburdened health services for these children. The complexity of and lack of continuity within services, family lives, social expectations and hierarchies provided the context and conditions for children's, often complex, illness trajectories. Parents reported powerlessness and perceived criticism leading to delayed help-seeking. Importantly, parents and professionals missed symptoms of serious illness. Risk averse services were found to refer more children to emergency departments. CONCLUSIONS: Parents and professionals have difficulties recognising signs of SII in young children and can feel socially constrained from seeking help. The increased burden on services has made it more difficult for professionals to spot the seriously ill child.
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Doenças Transmissíveis , Pais , Pré-Escolar , Família , Teoria Fundamentada , Humanos , Estudos Retrospectivos , IncertezaRESUMO
Background Radiation therapy (RT)-associated oral mucositis, xerostomia, thick mucoid saliva, nausea/vomiting, and loss of taste may result in significantly compromised oral intake in patients undergoing treatment for head and neck cancers (HNC). Feeding tube placement allows patients to receive enteral nutrition and continue the planned course of treatment. Objectives RT-associated oral mucositis, xerostomia, and loss of taste may result in significantly compromised oral intake in patients undergoing treatment for head and neck cancers. We sought to determine if reactive nasogastric (NG) tube placement was an effective strategy for nutritional support in these patients and if invasive percutaneous endoscopic gastrostomy (PEG) tube insertion could be avoided. Methods This is an institutional review board (IRB)-approved study of patients treated for head and neck cancer using definitive or adjuvant RT with or without concurrent chemotherapy between June 2017 and December 2020. We evaluated the indications for NG tube (Dobhoff) placement, time of placement during the course of RT, patient tolerance of NG tube, and median duration of NG tube placement. In addition, we followed weight loss during treatment, treatment interruptions, and treatment-related toxicities. Complications associated with having the NG tube, if the NG tube needed to be replaced during treatment, and if the patient had any hospitalization during the course of treatment were tracked. Results Of the 441 patients treated for head and neck cancer during the time period of this study, 47 required reactive NG tube placement for nutritional support. Patients included 40 with primary oropharynx, three with oral cavity, two with larynx, one with nasopharyngeal, and one was unknown. Chemotherapy was given concurrently with radiation in 87.2% (n=41) patients. The median time of NG tube placement was during Week 5 of the six to seven-week course of RT. The median percentage of weight loss from baseline to the date of NG tube placement was 12.9% (range, -0.9% to 25.9%). The median rate of weight loss decreased by 8.7% from the date of NG tube placement to the end of treatment. The median duration of NG tube placement was 29 days (range, 5 to 151 days). There were no serious medical complications associated with having the NG tube in place during treatment. Twenty-seven point six percent (27.6%; n=13) of patients had the NG tube dislodged or displaced and needed replacement. Thirty-eight point three percent (38.3%; n=18) of patients with an NG tube had to be hospitalized during the course of RT, with the predominant symptoms being failure to thrive (22.2%; n=4) and nausea/vomiting 22.2% (n=4). Six point four percent (6.4%; n=3) of patients requested the removal of the NG tube due to local irritation. Seventy-six point six percent (76.6%; n=36) of patients did not require further nutritional support with the placement of a percutaneous endoscopic gastrostomy (PEG) tube. Conclusion This study indicates that clinic placement of an NG tube for patients receiving RT for head and neck cancer is a safe and effective way to maintain nutrition during treatment. The rate of weight loss decreased after the patient had an NG tube placed. The placement procedure is well-tolerated and there were no complications associated withâ¯having the NG tube during treatment. PEG tube insertion was avoided in approximately 80% of the patients.
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BACKGROUND: Repeat expansion disorders affect about 1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in underdiagnosis of people who have atypical clinical presentations, especially in paediatric patients without a previous positive family history. Whole genome sequencing is increasingly used as a first-line test for other rare genetic disorders, and we aimed to assess its performance in the diagnosis of patients with neurological repeat expansion disorders. METHODS: We retrospectively assessed the diagnostic accuracy of whole genome sequencing to detect the most common repeat expansion loci associated with neurological outcomes (AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, C9orf72, CACNA1A, DMPK, FMR1, FXN, HTT, and TBP) using samples obtained within the National Health Service in England from patients who were suspected of having neurological disorders; previous PCR test results were used as the reference standard. The clinical accuracy of whole genome sequencing to detect repeat expansions was prospectively examined in previously genetically tested and undiagnosed patients recruited in 2013-17 to the 100â000 Genomes Project in the UK, who were suspected of having a genetic neurological disorder (familial or early-onset forms of ataxia, neuropathy, spastic paraplegia, dementia, motor neuron disease, parkinsonian movement disorders, intellectual disability, or neuromuscular disorders). If a repeat expansion call was made using whole genome sequencing, PCR was used to confirm the result. FINDINGS: The diagnostic accuracy of whole genome sequencing to detect repeat expansions was evaluated against 793 PCR tests previously performed within the NHS from 404 patients. Whole genome sequencing correctly classified 215 of 221 expanded alleles and 1316 of 1321 non-expanded alleles, showing 97·3% sensitivity (95% CI 94·2-99·0) and 99·6% specificity (99·1-99·9) across the 13 disease-associated loci when compared with PCR test results. In samples from 11â631 patients in the 100â000 Genomes Project, whole genome sequencing identified 81 repeat expansions, which were also tested by PCR: 68 were confirmed as repeat expansions in the full pathogenic range, 11 were non-pathogenic intermediate expansions or premutations, and two were non-expanded repeats (16% false discovery rate). INTERPRETATION: In our study, whole genome sequencing for the detection of repeat expansions showed high sensitivity and specificity, and it led to identification of neurological repeat expansion disorders in previously undiagnosed patients. These findings support implementation of whole genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder. FUNDING: Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, and Illumina.
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Expansão das Repetições de DNA , Medicina Estatal , Criança , Proteína do X Frágil da Deficiência Intelectual/genética , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Reino Unido , Sequenciamento Completo do Genoma/métodosRESUMO
Previous studies have described reverse-transcription loop-mediated isothermal amplification (RT-LAMP) for the rapid detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in nasopharyngeal/oropharyngeal swab and saliva samples. This multisite clinical evaluation describes the validation of an improved sample preparation method for extraction-free RT-LAMP and reports clinical performance of four RT-LAMP assay formats for SARS-CoV-2 detection. Direct RT-LAMP was performed on 559 swabs and 86,760 saliva samples and RNA RT-LAMP on extracted RNA from 12,619 swabs and 12,521 saliva samples from asymptomatic and symptomatic individuals across health care and community settings. For direct RT-LAMP, overall diagnostic sensitivity (DSe) was 70.35% (95% CI, 63.48%-76.60%) on swabs and 84.62% (95% CI, 79.50%-88.88%) on saliva, with diagnostic specificity of 100% (95% CI, 98.98%-100.00%) on swabs and 100% (95% CI, 99.72%-100.00%) on saliva, compared with quantitative RT-PCR (RT-qPCR); analyzing samples with RT-qPCR ORF1ab CT values of ≤25 and ≤33, DSe values were 100% (95% CI, 96.34%-100%) and 77.78% (95% CI, 70.99%-83.62%) for swabs, and 99.01% (95% CI, 94.61%-99.97%) and 87.61% (95% CI, 82.69%-91.54%) for saliva, respectively. For RNA RT-LAMP, overall DSe and diagnostic specificity were 96.06% (95% CI, 92.88%-98.12%) and 99.99% (95% CI, 99.95%-100%) for swabs, and 80.65% (95% CI, 73.54%-86.54%) and 99.99% (95% CI, 99.95%-100%) for saliva, respectively. These findings demonstrate that RT-LAMP is applicable to a variety of use cases, including frequent, interval-based direct RT-LAMP of saliva from asymptomatic individuals who may otherwise be missed using symptomatic testing alone.
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COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , Teste para COVID-19 , Humanos , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , RNA Viral/análise , RNA Viral/genética , SARS-CoV-2/genética , Saliva , Sensibilidade e EspecificidadeRESUMO
BACKGROUND Kawasaki disease (KD) is an acute inflammatory vasculitis, which occurs mostly in childhood, predominantly between the ages of 6 months and 5 years. The incidence of coronary artery abnormalities associated with KD has decreased from 25% to 4% as a result of timely diagnosis and treatment with intravenous immunoglobulin (IVIG). Infants ≤6 months of age are the most likely to develop prolonged fever without the other clinical criteria for KD, and diagnosis can sometimes be challenging or delayed. They are therefore at particularly high risk of developing coronary artery abnormalities. CASE REPORT A 2-month-old male infant with no significant medical history initially presented with a history of nasal congestion, right conjunctivitis, red lips, and 1 loose stool in the pre-COVID-19 era. He was diagnosed with otitis media and was started on oral amoxicillin. By day 7 of fever, he had developed symptoms and signs and laboratory findings consistent with Kawasaki disease, which is rare in this age group. His echocardiogram showed dilated proximal left anterior descending and right coronary arteries. He was successfully treated, and his most recent echocardiogram, performed 17 months after his treatment, showed remarkable improvement in the coronary arteries. CONCLUSIONS Kawasaki disease in children less than 6 months of age is still rare, and the presentation can sometimes make the diagnosis somewhat challenging. Increased clinical suspicion is required for recognition in the youngest patients, as they are more likely to present with few features of KD. Early diagnosis and treatment are needed to prevent or minimize the risk of significant coronary artery abnormalities.
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COVID-19 , Doença da Artéria Coronariana , Síndrome de Linfonodos Mucocutâneos , Criança , Vasos Coronários/diagnóstico por imagem , Dilatação , Humanos , Lactente , Masculino , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , SARS-CoV-2RESUMO
Clinical validity assessments of gene-disease associations underpin analysis and reporting in diagnostic genomics, and yet wide variability exists in practice, particularly in use of these assessments for virtual gene panel design and maintenance. Harmonization efforts are hampered by the lack of agreed terminology, agreed gene curation standards, and platforms that can be used to identify and resolve discrepancies at scale. We undertook a systematic comparison of the content of 80 virtual gene panels used in two healthcare systems by multiple diagnostic providers in the United Kingdom and Australia. The process was enabled by a shared curation platform, PanelApp, and resulted in the identification and review of 2,144 discordant gene ratings, demonstrating the utility of sharing structured gene-disease validity assessments and collaborative discordance resolution in establishing national and international consensus.
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Consenso , Curadoria de Dados/normas , Doenças Genéticas Inatas/genética , Genômica/normas , Anotação de Sequência Molecular/normas , Austrália , Biomarcadores/metabolismo , Curadoria de Dados/métodos , Atenção à Saúde , Expressão Gênica , Ontologia Genética , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/patologia , Genômica/métodos , Humanos , Aplicativos Móveis/provisão & distribuição , Terminologia como Assunto , Reino UnidoRESUMO
OBJECTIVES: Rapid, high throughput diagnostics are a valuable tool, allowing the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in populations so as to identify and isolate people with asymptomatic and symptomatic infections. Reagent shortages and restricted access to high throughput testing solutions have limited the effectiveness of conventional assays such as quantitative RT-PCR (RT-qPCR), particularly throughout the first months of the coronavirus disease 2019 pandemic. We investigated the use of LamPORE, where loop-mediated isothermal amplification (LAMP) is coupled to nanopore sequencing technology, for the detection of SARS-CoV-2 in symptomatic and asymptomatic populations. METHODS: In an asymptomatic prospective cohort, for 3 weeks in September 2020, health-care workers across four sites (Birmingham, Southampton, Basingstoke and Manchester) self-swabbed with nasopharyngeal swabs weekly and supplied a saliva specimen daily. These samples were tested for SARS-CoV-2 RNA using the Oxford Nanopore LamPORE system and a reference RT-qPCR assay on extracted sample RNA. A second retrospective cohort of 848 patients with influenza-like illness from March 2020 to June 2020 were similarly tested from nasopharyngeal swabs. RESULTS: In the asymptomatic cohort a total of 1200 participants supplied 23 427 samples (3966 swab, 19 461 saliva) over a 3-week period. The incidence of SARS-CoV-2 detection using LamPORE was 0.95%. Diagnostic sensitivity and specificity of LamPORE was >99.5% (decreasing to approximately 98% when clustered estimation was used) in both swab and saliva asymptomatic samples when compared with the reference RT-qPCR test. In the retrospective symptomatic cohort, the incidence was 13.4% and the sensitivity and specificity were 100%. CONCLUSIONS: LamPORE is a highly accurate methodology for the detection of SARS-CoV-2 in both symptomatic and asymptomatic population settings and can be used as an alternative to RT-qPCR.
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COVID-19/diagnóstico , Técnicas de Diagnóstico Molecular/métodos , Técnicas de Amplificação de Ácido Nucleico/métodos , Pandemias , SARS-CoV-2/isolamento & purificação , COVID-19/virologia , Estudos de Coortes , Proteínas do Nucleocapsídeo de Coronavírus/genética , Humanos , Limite de Detecção , Sequenciamento por Nanoporos , Nasofaringe/virologia , Poliproteínas/genética , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos , SARS-CoV-2/genética , Saliva/virologia , Sensibilidade e Especificidade , Proteínas Virais/genéticaRESUMO
Despite increasing interest in pharmacogenomics, and the potential benefits to improve patient care, implementation into clinical practice has not been widespread. Recently, there has been a drive to implement genomic medicine into the UK National Health Service (NHS), largely spurred on by the success of the 100,000 Genomes Project. The UK Pharmacogenetics and Stratified Medicine Network, NHS England and Genomics England invited experts from academia, the healthcare sector, industry and patient representatives to come together to discuss the opportunities and challenges of implementing pharmacogenomics into the NHS. This report highlights the discussions of the workshop to provide an overview of the issues that need to be considered to enable pharmacogenomic medicine to become mainstream within the NHS.
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Farmacogenética/estatística & dados numéricos , Medicina Estatal , Biologia Computacional , Tratamento Farmacológico , Educação Médica , Registros Eletrônicos de Saúde , Testes Genéticos , Humanos , Educação de Pacientes como Assunto , Farmacogenética/educação , Medicina de Precisão , Reino UnidoRESUMO
The kinase-activating mutation G2019S in leucine-rich repeat kinase 2 (LRRK2) is one of the most common genetic causes of Parkinson's disease (PD) and has spurred development of LRRK2 inhibitors. Preclinical studies have raised concerns about the safety of LRRK2 inhibitors due to histopathological changes in the lungs of nonhuman primates treated with two of these compounds. Here, we investigated whether these lung effects represented on-target pharmacology and whether they were reversible after drug withdrawal in macaques. We also examined whether treatment was associated with pulmonary function deficits. We conducted a 2-week repeat-dose toxicology study in macaques comparing three different LRRK2 inhibitors: GNE-7915 (30 mg/kg, twice daily as a positive control), MLi-2 (15 and 50 mg/kg, once daily), and PFE-360 (3 and 6 mg/kg, once daily). Subsets of animals dosed with GNE-7915 or MLi-2 were evaluated 2 weeks after drug withdrawal for lung function. All compounds induced mild cytoplasmic vacuolation of type II lung pneumocytes without signs of lung degeneration, implicating on-target pharmacology. At low doses of PFE-360 or MLi-2, there was ~50 or 100% LRRK2 inhibition in brain tissue, respectively, but histopathological lung changes were either absent or minimal. The lung effect was reversible after dosing ceased. Lung function tests demonstrated that the histological changes in lung tissue induced by MLi-2 and GNE-7915 did not result in pulmonary deficits. Our results suggest that the observed lung effects in nonhuman primates in response to LRRK2 inhibitors should not preclude clinical testing of these compounds for PD.
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Doença de Parkinson , Animais , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Pulmão , Morfolinas , Mutação , Primatas , Pirimidinas , PirróisRESUMO
Foreign Body Airway Obstruction (FBAO) is a medical emergency that can result in death, particularly if swift, appropriate action is not taken. It can be a frightening experience for all involved. DeChoker, an Airway Clearance Device (ACD), might provide an additional alternative in the management of choking; however, limited evidence around its safety and effectiveness makes adoption controversial. Objectives: An independent evaluation to explore the experiences of health and care professionals who used DeChoker in real-life adult choking emergencies, focusing on the product's safety, efficacy and ease of application. Design: Retrospective mixed methods case study, with multiple embedded units of analysis. Setting: UK adult care homes. Participants: Twenty seven incidents of adult choking emergencies self-reported by care home staff where DeChoker was used. This data was augmented by an in-depth exploration of four individual choking incidences. Results: The choking victim's ages range: 45 to 101 years (mean 79.8 years). The device was reported to have successfully removed the obstruction in 26 of 27 cases, with very few complications or adverse events reported. In 21 of 27 incidents (78%) the victim was not required to visit Accident and Emergency. Qualitative data indicated nursing home staff found the DeChoker easy to use and valued its presence as an adjunct to current guideline procedures. Conclusion: There is a dearth of evidence surrounding the management of choking and little innovation in this area for five decades. This retrospective evaluation contributes to discussion regarding the role ACDs might play in the management of choking, particularly in cases where current choking management guidance are ineffective, insufficient, inappropriate or impractical (e.g., frail or movement restricted people). The interview data presents a view from care home staff that the DeChoker, as an ACD, contributed to saving the life of choking victims.