2 Minute Medicine Rewind April 27, 2020

Viral Load Dynamics and Disease Severity In Patients Infected With SARS-CoV-2 In Zhejiang Province, China, January-March 2020: Retrospective Cohort Study

1. Stool samples demonstrated significantly longer duration of positive viral load than both respiratory and serum samples.

2. Length of positive RNA detection was associated with disease duration with a peak later in respiratory samples of those with severe disease compared to those with mild disease.

Evidence Rating Level: 2 (Good)

A total of 190 countries have been impacted by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as of March 22, 2020, resulting in over 300,000 confirmed cases and 14,510 deaths. In China specifically, approximately 13.8% of those infected become severely ill and 2.3% eventually pass away. Viral load measurements via tissue samples assist with monitoring progression, response to treatment, remission, and relapse. This retrospective cohort study aimed to estimate viral loads in 3,497 samples obtained from 96 patients following admission with confirmed SARS-CoV-2 and analyze temporal changes in viral loads based on sample types and disease severity. Respiratory (sputum or saliva), stool, serum, and urine samples were collected following admission and whenever possible thereafter to examine the amount of SARS-CoV-2 RNA by polymerase chain reaction (PCR) analysis. RNA was detected in stool samples of 59% of participants and in the serum of 41% of participants; urine from only one participant was positive for the virus. The median duration of SARS-CoV-2 in respiratory samples (18 days) and serum samples (16 days) were significantly shorter than in stool samples (22 days, p = 0.02, p<0.001, respectively). Disease severity was also associated with median duration of the virus in samples. Respiratory samples of participants with severe disease were positive for median duration significantly longer (21 days) than those with mild disease (14 days, p = 0.04). Within this mild group, though, viral loads seemed to peak in respiratory samples in the second week while they remained stable and high during the third week in the severe disease group. Risk factors for increased length of viral load detection included age (>60 years) and gender (male).

Febuxostat Does Not Delay Progression of Carotid Atherosclerosis In Patients With Asymptomatic Hyperuricemia: A Randomized, Controlled Trial

1. While there was no placebo control group, treatment with febuxostat for 24 months did not slow carotid atherosclerosis progression in Japanese individuals with asymptomatic hyperuricemia.

Evidence Rating Level: 2 (Good)

Allopurinol, a purine analogue xanthine oxidase (XO) inhibitor, is a conventional pharmacological intervention for reducing serum uric acid (SUA) levels, which increases risk of cardiovascular disease. Febuxostat, a novel non-purine selective inhibitor of XO, has been found to have greater efficacy in lowering urate and a higher potency for XO inhibition. However, little is known regarding febuxostat and its role in atherosclerosis. This prospective, randomized, open-label, blinded-endpoint clinical trial occurring at 48 sites in Japan between May 2014 and August 2018 sought to examine the relationship between febuxostat and atherosclerosis through measuring carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. A total of 483 adult participants (mean [SD] age = 69.1 [10.4] years, 19.7% female) with both maximum IMT of common carotid artery (CCA; ≥ 1.1 mm) and asymptomatic hyperuricemia (SUA ≥ 7.0 mg/dL) were allocated to either dose-titrated febuxostat (n = 239; 10 to 60 mg daily) or a non-pharmacological lifestyle modification for hyperuricemia (n = 244; e.g., diet, exercise changes) based on an intention-to-treat principle. Primary endpoint was change in mean IMT of the CCA from baseline to 24 months, with age, gender, history of type II diabetes, baseline SUA and IMT of the CCA as covariates. No significant differences between groups regarding CCA-IMT were found at baseline (p = 0.65). At 24 months, between group differences were not significant(mean difference -0.016 mm, 95% CI -0.051 to 0.019 mm, p = 0.37). Febuxostat did not demonstrate significant effects on the primary endpoint compared to the control group, nor did it have effects on other carotid ultrasonographic parameters. Regarding mean SUA values at 24 months, the febuxostat group was significantly lower than the control group (mean difference -2.62, 95% CI -2.86 to -2.38, p<0.001). While this study did not include a placebo control group, findings still suggest that 24 months of febuxostat treatment did not slow carotid atherosclerosis progression in Japanese individuals with asymptomatic hyperuricemia.

Mood Homeostasis, Low Mood, and History of Depression in 2 Large Population Samples

1. Mood homeostasis, or the preferential ability to engage in adequate mood-modifying behaviors, is associated with mean mood and history of depression.

2. Individuals with low mean mood had significantly lower mood homeostasis scores than those with higher mean moods. This relationship was also found among those who had a history of depression compared to those without such histories.

Evidence Rating Level: 2 (Good)

Major depressive disorder (MDD) is the world’s leading cause of disability, with increasing evidence of substantial heterogeneity in terms of presentations and treatment outcomes. This examination of two case-control studies of 58,328 participants across countries of low, middle, and high income sought to investigate impaired mood homeostasis and its associations with low mood and a history of MDD. The first data set, (58sec data set) recruited young adults (mean [SD] age = 28.1 [9.0] years, 65.8% female) in high-income francophone countries. The second data set (World Health Organization Study on Global Aging and Adult Health [WHO SAGE] data set) included representative samples from Ghana, China, India, Russia, Mexico, and South Africa (mean [SD] age = 57.8 [14.7] years, 57.0% female). Impaired mood homeostasis was defined as “the extent to which a person preferentially engages in mood-increasing activities such as exercising when their mood is low and saves the mood-decreasing activities such as house-work for when their mood is higher.” Through the use of self-report data pertaining to mood homeostasis, it was determined that participants with low mean mood reported significantly lower levels of mood homeostasis (0.63, 95% CI 0.45 to 0.79) compared to those with high mean mood (0.96, 95% CI 0.96 to 0.98, p<0.001). Individuals with a history of MDD also had lower levels of mood homeostasis (0.03, 95% CI -0.26 to 0.24) than those without a history of MDD (0.68, 95% CI 0.55 to 0.75, p<0.001). Lower mood homeostasis was found to lead to a greater number of depressive episodes (difference 8.0% annual risk, p<0.001) as well as longer durations of these episodes (difference 1.29 weeks, p = 0.006) in dynamic simulations. The findings of this study suggest that mood homeostasis may serve a meaningful role in better understanding the heterogeneity of MDD. Those with a history of MDD and/or low mean mood should be assessed for impaired mood homeostasis.

Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study

1. Two novel gene loci among Asian populations were identified and associated with Parkinson’s disease (SV2C, WBSCR17) that had not been previously included in European loci or polygenic risk score models.

Evidence Rating Level: 1 (Excellent)

Parkinson’s disease (PD) is a leading age-related neurodegenerative disease and cause of death, resulting in over 200,000 deaths and substantial disability globally. It is a heterogenous disease with several genes and pathways are involved in its pathogenesis. This genome-wide association study (GWAS) aimed to identify novel loci for PD among Asian participants and then compare the findings to European cohorts. Data was collected from January 1, 2016 to December 31, 2018 from the following Asian countries: Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea. Replication of top loci in Japanese and European samples was performed as part of this study. A total of 31,575 samples were identified with 6,724 PD cases (mean [SD] age = 64.3 [10] years, age [SD] of onset = 58.8 [10.6] years, 46.8% female) and 24,851 controls (mean [SD] age = 59.4 [11.4] years, 55% female). Eleven genome-wide significant loci were identified, two of which were novel (SV2C and WVSCR17) and nine that had been found among Europeans previously. Subsequent replication with European and Japanese groups found significant associations for SV2C (rs246814; OR 1.16, 95% CI 1.11 to 1.21, p = 1.17×10-10). However, genetic heterogeneity was found at WBSCR17 (rs9638616; I2 = 67.1%, p = 0.00340). Models of polygenic risk scores were improved in terms of the area under the curve compared to the 78 European loci on their own (difference 2.9%, p = 6.81×10-12). Overall, this study suggests that Asian populations demonstrate two novel gene loci associated with PD that could allow for better stratification of this population based on current polygenic risk scores.

Evaluation of Medical Surveillance and Incidence of Post-September 11, 2001, Thyroid Cancer in World Trade Center-Exposed Firefighters and Emergency Medical Service Workers

1. Fire Department World Trade Center-exposed workers demonstrate more asymptomatic thyroid cancers, attributable to occult lesion diagnoses, compared to non-WTC-exposed subjects of the Rochester Epidemiology Project and the general US population.

Evidence Rating Level: 2 (Good)

Incidence rates of thyroid cancer have increased by approximately 300% over the past 40 years, such that it is one of the most common forms of cancer diagnosed in the US. This increase is thought to be related to asymptomatic lesions, along with environmental exposures to harmful elements. This closed-cohort study examined the association between thyroid cancer and World Trade Center (WTC) exposure among rescue and recovery workers. These workers included 14,987 men from the Fire Department of the City of New York WTC-exposed cohort, with both asymptomatic (median [IQR] age at diagnosis = 50.2 [44.0 to 58.6] years) and symptomatic (median [IQR] age at diagnosis = 46.6 [43.9 to 52.9] years) detection methods of thyroid cancer. A total of 72 cases of thyroid cancer were detected, 65 of which had a categorized detection method and was used in further analyses. Approximately 81.5% were asymptomatic and 18.5% were symptomatic. Papillary thyroid cancer accounted for 98.1% of all cancers with a detection method and only one case of follicular carcinoma was found. Compared to the Rochester Epidemiology Project, the overall age-standardized incidence of thyroid cancer of those 20 years or older was greater in the Fire Department cohort (difference 14.3), which were accounted for by asymptomatic cancers. Post-9/11 thyroid cancer incidence among the Fire Department was double that of the Rochester Epidemiology Project (RR 2.3, 95% CI 1.7 to 3.2). While the relative rates of thyroid cancer in the Fire Department were not significantly different than those of the Rochester Epidemiology Project (RR 0.8, 95% CI 0.4 to 1.5), the rate of asymptomatic cancers among the Fire Department was three times greater than the Rochester Epidemiology Project (RR 3.1, 95% CI 2.1 to 4.7). Overall, this study suggests that thyroid cancer rates in WTC-exposed workers are higher than both non-WTC-exposed subjects of the Rochester Epidemiology Project as well as the US population but this difference may be secondary to increased surveillance. Limitations include the exclusion of women, lack of a non-WTC-exposed Fire Department group, and potential differential misclassification.

Image: PD

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