RESUMEN
AIMS: For diseases with a genetic cause, genomics can deliver improved diagnostics and facilitate access to targeted treatments. Drug pharmacodynamics and pharmacokinetics are often dependent on genetic variation underlying these processes. As pharmacogenomics comes of age, it may be the first way in which genomics is utilised at a population level. Still required is guidance and standards of how genomic information can be communicated within the health record, and how clinicians should be alerted to variation impacting the use of medicines. METHODS: The Professional Record Standards Body commissioned by NHS England developed guidance on using pharmacogenomics information in clinical practice. We conducted research with those implementing pharmacogenomics in England and internationally to produce guidance and recommendations for a systems-based approach. RESULTS: A consensus viewpoint is that systems need to be in place to ensure the safe provision of pharmacogenomics information that is curated, actionable and up-to-date. Standards should be established with respect to notification and information exchange, which could impact new or existing prescribing and these must be in keeping with routine practice. Alerting systems should contribute to safer practices. CONCLUSION: Ensuring pharmacogenetics information is available to make safer use of medicines will require a major effort, of which this guidance is a beginning. Standards are required to ensure useful genomic information within the health record can be communicated to clinicians in the right format and at the right times to be actioned successfully. A multidisciplinary group of stakeholders must be engaged in developing pharmacogenomic standards to support the most appropriate prescribing.
Asunto(s)
Registros Electrónicos de Salud , Farmacogenética , Atención a la Salud , Genómica , Personal de Salud , Humanos , Farmacogenética/métodosRESUMEN
BACKGROUND: Despite the availability of effective drug therapies that reduce low-density lipoprotein (LDL)-cholesterol (LDL-C), cardiovascular disease (CVD) remains an important cause of mortality and morbidity. Therefore, additional LDL-C reduction may be warranted, especially for people who are unresponsive to, or unable to take, existing LDL-C-reducing therapies. By inhibiting the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme, monoclonal antibodies (PCSK9 inhibitors) reduce LDL-C and CVD risk. OBJECTIVES: Primary To quantify the effects of PCSK9 inhibitors on CVD, all-cause mortality, myocardial infarction, and stroke, compared to placebo or active treatment(s) for primary and secondary prevention. Secondary To quantify the safety of PCSK9 inhibitors, with specific focus on the incidence of influenza, hypertension, type 2 diabetes, and cancer, compared to placebo or active treatment(s) for primary and secondary prevention. SEARCH METHODS: We identified studies by systematically searching CENTRAL, MEDLINE, Embase, and Web of Science in December 2019. We also searched ClinicalTrials.gov and the International Clinical Trials Registry Platform in August 2020 and screened the reference lists of included studies. This is an update of the review first published in 2017. SELECTION CRITERIA: All parallel-group and factorial randomised controlled trials (RCTs) with a follow-up of at least 24 weeks were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed and extracted data. Where data were available, we calculated pooled effect estimates. We used GRADE to assess certainty of evidence and in 'Summary of findings' tables. MAIN RESULTS: We included 24 studies with data on 60,997 participants. Eighteen trials randomised participants to alirocumab and six to evolocumab. All participants received background lipid-lowering treatment or lifestyle counselling. Six alirocumab studies used an active treatment comparison group (the remaining used placebo), compared to three evolocumab active comparison trials. Alirocumab compared with placebo decreased the risk of CVD events, with an absolute risk difference (RD) of -2% (odds ratio (OR) 0.87, 95% confidence interval (CI) 0.80 to 0.94; 10 studies, 23,868 participants; high-certainty evidence), decreased the risk of mortality (RD -1%; OR 0.83, 95% CI 0.72 to 0.96; 12 studies, 24,797 participants; high-certainty evidence), and MI (RD -2%; OR 0.86, 95% CI 0.79 to 0.94; 9 studies, 23,352 participants; high-certainty evidence) and for any stroke (RD 0%; OR 0.73, 95% CI 0.58 to 0.91; 8 studies, 22,835 participants; high-certainty evidence). Compared to active treatment the alirocumab effects, for CVD, the RD was 1% (OR 1.37, 95% CI 0.65 to 2.87; 3 studies, 1379 participants; low-certainty evidence); for mortality, RD was -1% (OR 0.51, 95% CI 0.18 to 1.40; 5 studies, 1333 participants; low-certainty evidence); for MI, RD was 1% (OR 1.45, 95% CI 0.64 to 3.28, 5 studies, 1734 participants; low-certainty evidence); and for any stroke, RD was less than 1% (OR 0.85, 95% CI 0.13 to 5.61; 5 studies, 1734 participants; low-certainty evidence). Compared to placebo the evolocumab, for CVD, the RD was -2% (OR 0.84, 95% CI 0.78 to 0.91; 3 studies, 29,432 participants; high-certainty evidence); for mortality, RD was less than 1% (OR 1.04, 95% CI 0.91 to 1.19; 3 studies, 29,432 participants; high-certainty evidence); for MI, RD was -1% (OR 0.72, 95% CI 0.64 to 0.82; 3 studies, 29,432 participants; high-certainty evidence); and for any stroke RD was less than -1% (OR 0.79, 95% CI 0.65 to 0.94; 2 studies, 28,531 participants; high-certainty evidence). Compared to active treatment, the evolocumab effects, for any CVD event RD was less than -1% (OR 0.66, 95% CI 0.14 to 3.04; 1 study, 218 participants; very low-certainty evidence); for all-cause mortality, the RD was less than 1% (OR 0.43, 95% CI 0.14 to 1.30; 3 studies, 5223 participants; very low-certainty evidence); and for MI, RD was less than 1% (OR 0.66, 95% CI 0.23 to 1.85; 3 studies, 5003 participants; very low-certainty evidence). There were insufficient data on any stroke. AUTHORS' CONCLUSIONS: The evidence for the clinical endpoint effects of evolocumab and alirocumab were graded as high. There is a strong evidence base to prescribe PCSK9 monoclonal antibodies to people who might not be eligible for other lipid-lowering drugs, or to people who cannot meet their lipid goals on more traditional therapies, which was the main patient population of the available trials. The evidence base of PCSK9 inhibitors compared with active treatment is much weaker (low very- to low-certainty evidence) and it is unclear whether evolocumab or alirocumab might be effectively used as replacement therapies. Related, most of the available studies preferentially enrolled people with either established CVD or at a high risk already, and evidence in low- to medium-risk settings is minimal. Finally, there is very limited evidence on any potential safety issues of both evolocumab and alirocumab. While the current evidence synthesis does not reveal any adverse signals, neither does it provide evidence against such signals. This suggests careful consideration of alternative lipid lowering treatments before prescribing PCSK9 inhibitors.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , LDL-Colesterol/sangre , Inhibidores de PCSK9 , Anticolesterolemiantes/uso terapéutico , Causas de Muerte , Antagonistas Colinérgicos/uso terapéutico , Ezetimiba/uso terapéutico , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Prevención Primaria/métodos , Proproteína Convertasa 9/inmunología , Ensayos Clínicos Controlados Aleatorios como Asunto , Prevención Secundaria/métodos , Accidente Cerebrovascular/epidemiología , Factores de TiempoRESUMEN
A male patient aged in his early twenties presented to the emergency department (ED) with quadriparesis. He was ordinarily fit and well and had exercised and eaten a carbohydrate rich meal the evening before. His point-of-care venous blood sample on arrival to the ED showed hypokalaemia of 1.6 mmol/L. (normal range=3.5-5.0 mmol/L). He was put on a cardiac monitor and started on an intravenous infusion of potassium chloride. With the benefit of hindsight, his male sex, particular features in his history and his initial ECG all pointed to a differential diagnosis of thyrotoxic periodic paralysis (TPP), although a differential diagnosis of a first attack of familial hypokalaemic paralysis was considered. As urgent thyroid function tests were sent promptly, there was minimal delay in reaching a diagnosis of TPP and promptly starting propranolol as a safe and more effective means of reversing TPP, followed by definitive treatment with carbimazole.
Asunto(s)
Parálisis Periódica Hipopotasémica , Tirotoxicosis , Anciano , Servicio de Urgencia en Hospital , Humanos , Parálisis Periódica Hipopotasémica/diagnóstico , Parálisis Periódica Hipopotasémica/tratamiento farmacológico , Masculino , Parálisis/diagnóstico , Potasio , Tirotoxicosis/complicaciones , Tirotoxicosis/diagnóstico , Tirotoxicosis/tratamiento farmacológicoRESUMEN
A 36-year-old man was brought to the emergency department with suspected COVID-19, following a 3-week history of cough, fevers and shortness of breath, worsening suddenly in the preceding 4 hours. On presentation he was hypoxaemic, with an SpO2 of 88% on 15 L/min oxygen, tachycardic and had no audible breath sounds on auscultation of the left hemithorax. Local guidelines recommended that the patient should be initiated on continuous positive airway pressure while investigations were awaited, however given the examination findings an emergency portable chest radiograph was performed. The chest radiograph demonstrated a left-sided tension pneumothorax. This was treated with emergency needle decompression, with good effect, followed by chest drain insertion. A repeat chest radiograph demonstrated lung re-expansion, and the patient was admitted to a COVID-19 specific ward for further observation. This case demonstrates tension pneumothorax as a possible complication of suspected COVID-19 and emphasises the importance of thorough history-taking and clinical examination.
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Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Neumotórax/terapia , Adulto , COVID-19 , Tubos Torácicos , Infecciones por Coronavirus/diagnóstico , Humanos , Masculino , Pandemias , Neumonía Viral/diagnóstico , Neumotórax/etiología , ToracostomíaRESUMEN
Spinal muscular atrophy (SMA) is a recessive disease caused by mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), whose absence dramatically affects the survival of motor neurons. In humans, the severity of the disease is lessened by the presence of a gene copy, SMN2. SMN2 differs from SMN1 by a C-to-T transition in exon 7, which modifies pre-mRNA splicing and prevents successful SMN synthesis. Splice-switching approaches using antisense oligonucleotides (AONs) have already been shown to correct this SMN2 gene transition, providing a therapeutic avenue for SMA. However, AON administration to the CNS presents additional hurdles. In this study, we show that systemic delivery of tricyclo-DNA (tcDNA) AONs in a type III SMA mouse augments retention of exon 7 in SMN2 mRNA both in peripheral organs and the CNS. Mild type III SMA mice were selected as opposed to the severe type I model in order to test tcDNA efficacy and their ability to enter the CNS after maturation of the blood brain barrier (BBB). Furthermore, subcutaneous treatment significantly improved the necrosis phenotype and respiratory function. In summary, our data support that tcDNA oligomers effectively cross the blood-brain barrier and offer a promising systemic alternative for treating SMA.