2 Minute Medicine Rewind March 28th, 2022

Rapid Point-of-Care Genotyping to Avoid Aminoglycoside-Induced Ototoxicity in Neonatal Intensive Care

1. In a cohort of neonates, the MT-RNR1 rapid point-of-care test was utilized without disruption of clinical practice and the identified genotype was used to guide antibiotic prescription to avoid aminoglycoside induced ototoxicity. 

Evidence Rating Level: 2 (Good) 

In high doses, aminoglycoside antibiotics may cause nephrotoxicity or ototoxicity. Research has found that certain individuals with a mitochondrial genome variant have a predisposition to aminoglycoside-induced ototoxicity (AIO) whereby even a single dose could cause profound hearing loss. However, current genetic technologies are not sufficiently rapid to genotype the variant of concern, m.1555A>G, within an acute setting. Therefore, this study developed a rapid genotyping platform for the m.1555A>G variant and evaluated whether it could be implemented to avoid AIO without disrupting clinical practice on neonatal intensive care units (NICUs). This prospective trial collected and genotyped buccal samples (n=304) for preclinical assay validation from 159 individuals. The results demonstrated an assay sensitivity of 100% (95% CI, 93.9%-100%), specificity of 100% (95% CI, 98.5%-100%) and time to genotype of 26 minutes. The study recruited 751 neonates with median (range) age of 2.5 (0-198) days at the time of treatment. The median (SD) gestational age at time of delivery was 37 (4) weeks. Of those recruited, 526 neonates (70%) received antibiotics. The primary outcome measured was the number of neonates successfully tested for the m.1555A>G variant as a proportion of all infants who received aminoglycoside antibiotics. The study found that 424 (80.6%) of neonates prescribed aminoglycoside antibiotics were successfully tested for the m.1555A>G variant. The secondary outcomes measured were the total number of neonates identified with the genetic variant and whether they avoided aminoglycosides, the proportion of neonates where testing was not done, the median time to swab, and mean time to antibiotic administration. The study identified 3 neonates with the genetic variant and 153 neonates (20.4%) who were not successfully tested. The study also found no significant differences between the mean (SD) time to antibiotic therapy prior to implementation (55.87 [22.56] minutes) and post-implementation (55.18 [23.82] minutes; [95% CI, −5.96 to 4.23 minutes]). Overall, the study concluded that genotyping can be performed in the acute setting and incorporated into clinical practice without disrupting existing standards of care. However, this new technological approach needs to be further researched in larger scale and randomized studies to validate the results. 

Risk of first ischaemic stroke and use of antidopaminergic antiemetics: nationwide case-time-control study

1. In a cohort of adults from France, antidopaminergic antiemetic use was associated with an increased risk of ischemic stroke. 

Evidence Rating Level: 3 (Average) 

Prior studies have demonstrated a risk of ischemic stroke with centrally acting antidopaminergic antipsychotics in older adults and amongst patients with dementia. However, there is a lack of research on the risk of stroke for non-antipsychotic dopamine receptor antagonists, such as antidopaminergic antiemetics (ADA). Given the widespread use of ADAs in the treatment of nausea and vomiting, this case-control study sought to evaluate the association between ischemic stroke and ADAs. It made use of data from the French reimbursement healthcare system and 2612 participants with a first ischemic stroke were evaluated in the study (mean [SD] age, 71.9 [16.2] years; 33.9% [885/2612] men). The exposure was the administration of at least one antidopaminergic antiemetic (domperidone, metopimazine, or metoclopramide) during the observation period (70 days before the stroke). The 2612 participants included in the study all had matched controls. The primary outcome measured was the association between ADA use and risk of ischemic stroke, which was assessed by estimating the odds ratios of exposure evaluated in patients with stroke and in control. It was found that among the 2612 patients identified with incident stroke, 1250 received ADA in the risk period (defined as up to 14 days prior to the stroke), and 1060 in the reference period (up to 70 days before the stroke). The population of time trend controls included 21 859 individuals without an incidence of stroke. Among them, 5128 has received an ADA in the risk period and 13165 received an ADA in the reference period. The study found an adjusted odds ratio of 3.12 (95% CI, 2.85 – 3.42). Further analyses stratified by demographics such as age, sex, and history of dementia showed similar results. Specifically, the study calculated an adjusted odds ratio of 2.51 (95% CI, 2.18 – 2.88) for domperidone, 3.62 (95% CI, 3.11 – 4.23) for metopimazine, and 3.53 (95% CI, 2.62 – 4.76) for metoclopramide. Therefore, the study concluded that new users of ADA presented with an increased risk of stroke shortly after treatment started, with highest increase in risk for metopimazine and metoclopramide. However, the methodology for this study can only conclude correlation between ADA use and stroke. To further elucidate causation, multiple larger prospective trials are required. 

Ezetimibe combination therapy with statin for non-alcoholic fatty liver disease: an open-label randomized controlled trial (ESSENTIAL study)

1. In a group of individuals with non-alcoholic fatty liver disease, ezetimibe and rosuvastatin were found to be safe and significantly reduced liver fat. 

Evidence Rating Level: 1 (Excellent)

Non-alcoholic fatty liver disease (NAFLD) has been increasing in incidence across the world. Cholesterol has been found to contribute to the progression of non-alcoholic steatohepatitis (NASH) and the effects of anti-dyslipidemia therapies on NASH are currently being studied. However, there are not many studies evaluating the effects of ezetimibe. Therefore, this randomized controlled trial aimed to evaluate the effects of ezetimibe and statin combination therapy on NAFLD. The study included 70 participants with NAFLD (42.9% women) who were randomly assigned to either receive combination therapy (n = 34) or monotherapy (n = 36). Those receiving combination therapy were prescribed ezetimibe 10mg plus rosuvastatin 5mg daily for 24 weeks while patients in the monotherapy group were only given rosuvastatin 5mg daily for 24 weeks. The primary outcome measured was change in liver fat by MRI derived proton density fat fraction (MRI-PDFF). The study found that compared to baseline, there were significant reductions in end-of-treatment liver fat, as measured by the MRI-PDFF, for both combination therapy group (18.1% to 12.3%; p<0.001) and the monotherapy group (15.0% to 12.4%; p = 0.003). Specifically, the combination therapy was significantly better than the monotherapy in reducing liver fat (mean difference 3.2%; p = 0.020). The secondary outcomes measured were the change in liver fibrosis, measured by magnetic resonance elastography (MRE), change in insulin sensitivity, and changes in other parameters such as body weight and waist circumference. The study found that compared to baseline, there were no significant differences at end of treatment by MRE in either of the groups. The study found significant decreases in BMI, waist circumference, triglyceride, LDL cholesterol, and C-reactive protein (CRP) in both groups (all p<0.05). There were no significant adverse events reported in the study. Therefore, the study concluded that the use of ezetimibe in combination with rosuvastatin significantly improved hepatic steatosis and therefore is a safe and effective therapeutic option to treat patients with NAFLD and dyslipidemia. However, larger studies with increased sample size are needed to further validate this conclusion. 

Outcomes and Safety of History-Based Screening for Medication Abortion

1. In a cohort of patients with eligible abortions, screening for medication abortion eligibility by history alone was effective and safe, resulting in outcomes similar to models involving ultrasonography or pelvic examination. 

Evidence Rating Level: 2 (Good)

In the United States, medication abortion with mifepristone and misoprostol is currently approved for use through 70 days of pregnancy. During COVID-19, some clinics relied on history alone, without ultrasonography or a pelvic examination, to determine duration and location of pregnancy. Relying on history alone to determine eligibility of medication abortion will greatly increase accessibility to this service for many patients. Therefore, this multicenter retrospective cohort study assessed the effectiveness and safety of using history-based screening alone for medication abortion care. The study made use of data from 15 clinics and included 3779 patients with abortions. The primary outcomes measured in the study were effectiveness and safety. Effectiveness was defined as a binary measure of complete medication abortion after initial treatment without subsequent intervention. Safety was also defined as a binary measure of abortions not followed by a known abortion-related major adverse event (hospital admission, blood transfusion, major surgery, or death). The study found an overall adjusted effectiveness rate of 94.8% (95% CI, 93.6% – 95.9%). The adjusted rate of major abortion-related adverse events was 0.54% (95% CI, 0.18% – 0.90%). Overall, 12 major abortion-related adverse events occurred, including blood transfusions, hospital admissions and major surgical procedures. The secondary outcomes measured were incidence of ectopic pregnancy and retrospective determination that the initial medication abortion treatment had been provided at greater than 70 days of gestation. The study identified 4 ectopic pregnancies (0.22%; 95% CI, 0% – 0.45%). During follow-up, the study found 9 (0.40%; 95% CI, 0% – 0.84%) patients were found to have had pregnancy durations greater than 70 days at mifepristone dispensing although not identified at screening. The study concluded that the effectiveness rate of 95% is comparable to studies of medication abortion models with screening ultrasonography. Although the major adverse event rate (0.5%) was slightly higher than previous studies (0.2% – 0.3%), the results were not clinically significant. Therefore, it concluded history-based screening protocols are equally as effective and safe as those utilizing ultrasonography or pelvic examination at determining eligibility of medication abortion. Additional studies should be conducted in a randomized trial format to further validate these results. 

Comparison of the outcomes of EMS vs. Non-EMS transport of patients with ST-segment elevation myocardial infarction (STEMI) in Southern Iran: a population-based study

1. In a cohort of patients with ST-segment elevation myocardial infarctions from Iran, those transported using emergency medical services had lower death rates. 

Evidence Rating Level: 2 (Good)

ST-segment elevation myocardial infarctions (STEMI) are a leading cause of death worldwide, including Iran. Outcomes are highly dependent on time to treatment in these cardiac events, which has a direct correlation with patient transport time. Studies have demonstrated that utilizing emergency medical services (EMS) decreases the time spent transporting patients to hospital. In Iran, patients can choose different methods to go to medical centers, including EMS, private and public transport, yet, there has been no study conducted on their consequences. Therefore, this cross-sectional study aimed to compare the consequences of EMS versus non-EMS transport of patients with STEMI in Iran. This study made use of data from the Fasa Registry on Acute Myocardial Infarction. It included 2244 participants who were diagnosed with STEMI (1552 [69.16%] male; mean [SD] age, 55 [4.5] years). From this group, 934 (41.6%) utilized EMS services while 1310 (58.3%) utilized non-EMS transport. The study found a lower rate of death amongst patients transported using EMS versus those using non-EMS (33.95% vs. 66.86%; p < 0.001). Furthermore, the average time from the onset of symptoms to arrival in the hospital was 59.45 (24.73) minutes by ambulance and 48.75 (56.63) minutes by other vehicles. From this cohort, 169 (7.25%) patients died from the MI, from which 113 did not use EMS transport to the hospital. Therefore, the study concludes that the death rate in patients with acute MI who used EMS transport was lower than those who used non-EMS transport. This information can be utilized to take necessary public health measures to raise awareness about the use of EMS in Iran.   

Image: PD

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