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Corticosteroid Use and Risk of Herpes Zoster in a Population-Based Cohort

Author/s: 
Qian, J., Banks, E., Macartney, K., Heywood, A. E., Lassere, M. N., Liu, B.

Objective: To examine the relationship between corticosteroid use and herpes zoster risk.

Methods: With data from a large cohort of adults (the 45 and Up Study) recruited between 2006 and 2009 and linked to health data sets, the effect of corticosteroid use on zoster risk was analyzed by Cox proportional hazards models, adjusting for age, sex, and other characteristics.

Results: During 602,152 person-years (median, 7.36 years) of follow-up, there were 20,048 new systemic corticosteroid users and 6294 incident herpes zoster events among 94,677 participants (zoster incidence, 11.0 per 1000 person-years). Compared with nonusers, the risk of zoster was 59% higher in those using systemic corticosteroids (adjusted hazard ratio [aHR], 1.59; 95% CI, 1.48 to 1.71) and greater with higher cumulative doses: aHR of 1.32 (95% CI, 1.17 to 1.48), 1.74 (95% CI, 1.55 to 1.95), and 1.80 (95% CI, 1.61 to 2.02) for use of less than 500 mg, 500 mg to less than 1000 mg, and 1000 mg or more prednisolone equivalents, respectively (P value for trend, <.001). Compared with nonusers, zoster risk increased significantly (aHR, 6.00; 95% CI, 4.85 to 7.42) in the month after a single prescription of systemic corticosteroids and returned to levels similar to those in nonusers by the third month after dispensing (aHR, 0.91; 95% CI, 0.49 to 1.69).

Conclusion: Practitioners should be alert to the increased risk of zoster among patients taking systemic corticosteroids. Given the significant morbidity from zoster, particularly in older adults, these findings support judicious prescribing of corticosteroids, including using as low a dose and as short a course as possible.

Keywords: Cohort; Corticosteroids; Herpes zoster.

Keywords 
Cohort corticosteroids Herpes zoster

Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain

Author/s: 
McDonagh, M. S., Wagner, J., Ahmed, A. Y., Morasco, B., Kansagara, D., Chou, R.

Objectives. To evaluate the evidence on benefits and harms of cannabinoids and similar plant-based compounds to treat chronic pain.

Data sources. Ovid® MEDLINE®, PsycINFO®, Embase®, the Cochrane Library, and SCOPUS® databases, reference lists of included studies, submissions received after Federal Register request were searched to July 2021.

Review methods. Using dual review, we screened search results for randomized controlled trials (RCTs) and observational studies of patients with chronic pain evaluating cannabis, kratom, and similar compounds with any comparison group and at least 1 month of treatment or followup. Dual review was used to abstract study data, assess study-level risk of bias, and rate the strength of evidence. Prioritized outcomes included pain, overall function, and adverse events. We grouped studies that assessed tetrahydrocannabinol (THC) and/or cannabidiol (CBD) based on their THC to CBD ratio and categorized them as high-THC to CBD ratio, comparable THC to CBD ratio, and low-THC to CBD ratio. We also grouped studies by whether the product was a whole-plant product (cannabis), cannabinoids extracted or purified from a whole plant, or synthetic. We conducted meta-analyses using the profile likelihood random effects model and assessed between-study heterogeneity using Cochran’s Q statistic chi square and the I2 test for inconsistency. Magnitude of benefit was categorized into no effect or small, moderate, and large effects.

Results. From 2,850 abstracts, 20 RCTs (N=1,776) and 7 observational studies (N=13,095) assessing different cannabinoids were included; none of kratom. Studies were primarily short term, and 75 percent enrolled patients with a variety of neuropathic pain. Comparators were primarily placebo or usual care. The strength of evidence (SOE) was low, unless otherwise noted. Compared with placebo, comparable THC to CBD ratio oral spray was associated with a small benefit in change in pain severity (7 RCTs, N=632, 0 to10 scale, mean difference [MD] −0.54, 95% confidence interval [CI] −0.95 to −0.19, I2=28%; SOE: moderate) and overall function (6 RCTs, N=616, 0 to 10 scale, MD −0.42, 95% CI −0.73 to −0.16, I2=24%). There was no effect on study withdrawals due to adverse events. There was a large increased risk of dizziness and sedation and a moderate increased risk of nausea (dizziness: 6 RCTs, N=866, 30% vs. 8%, relative risk [RR] 3.57, 95% CI 2.42 to 5.60, I2=0%; sedation: 6 RCTs, N=866, 22% vs. 16%, RR 5.04, 95% CI 2.10 to 11.89, I2=0%; and nausea: 6 RCTs, N=866, 13% vs. 7.5%, RR 1.79, 95% CI 1.20 to 2.78, I2=0%). Synthetic products with high-THC to CBD ratios were associated with a moderate improvement in pain severity, a moderate increase in sedation, and a large increase in nausea (pain: 6 RCTs, N=390 to 10 scale, MD −1.15, 95% CI −1.99 to −0.54, I2=39%; sedation: 3 RCTs, N=335, 19% vs. 10%, RR 1.73, 95% CI 1.03 to 4.63, I2=0%; nausea: 2 RCTs, N=302, 12% vs. 6%, RR 2.19, 95% CI 0.77 to 5.39; I²=0%). We found moderate SOE for a large increased risk of dizziness (2 RCTs, 32% vs. 11%, RR 2.74, 95% CI 1.47 to 6.86, I2=0%). Extracted whole-plant products with high-THC to CBD ratios (oral) were associated with a large increased risk of study withdrawal due to adverse events (1 RCT, 13.9% vs. 5.7%, RR 3.12, 95% CI 1.54 to 6.33) and dizziness (1 RCT, 62.2% vs. 7.5%, RR 8.34, 95% CI 4.53 to 15.34). We observed a moderate improvement in pain severity when combining all studies of high-THC to CBD ratio (8 RCTs, N=684, MD −1.25, 95% CI −2.09 to −0.71, I2=50%; SOE: moderate). Evidence on whole-plant cannabis, topical CBD, low-THC to CBD, other cannabinoids, comparisons with active products, and impact on use of opioids was insufficient to draw conclusions. Other important harms (psychosis, cannabis use disorder, and cognitive effects) were not reported.

Conclusions. Low to moderate strength evidence suggests small to moderate improvements in pain (mostly neuropathic), and moderate to large increases in common adverse events (dizziness, sedation, nausea) and study withdrawal due to adverse events with high- and comparable THC to CBD ratio extracted cannabinoids and synthetic products in short-term treatment (1 to 6 months). Evidence for whole-plant cannabis, and other comparisons, outcomes, and PBCs were unavailable or insufficient to draw conclusions. Small sample sizes, lack of evidence for moderate and long-term use and other key outcomes, such as other adverse events and impact on use of opioids during treatment, indicate that more research is needed.

Initial Invasive or Conservative Strategy for Stable Coronary Disease

Author/s: 
Maron, DJ, Hochman, JS, Reynolds, HR, Bangalore, S, O'Brien, SM, Boden, WE, Chaitman, BR, Senior, R, Lopez-Sendon, J, Alexander, KP, Lopes, RD, Shaw, LJ, Berger, JS, Newman, JD, Sidhu, MS, Goodman, SG, Ruzyllo, W, Gosselin, G, Maggioni, AP, White, HD, Bhargava, B, Min, JK, Mancini, GBJ, Berman, DS, Picard, MH, Kwong, RY, Ali, ZA, Mark, DB, Spertus, JA, Krishnan, MN, Elghamaz, A, Moorthy, N, Hueb, WA, Demkow, M, Mavromatis, K, Bockeria, O, Peteiro, J, Miller, TD, Szwed, H, Doerr, R, Keltai, M, Selvanayagam, JB, Steg, PG, Held, C, Kohsaka, S, Mavromichalis, S, Kirby, R, Jeffries, NO, Harrell, FE Jr, Rockhold, FW, Broderick, S, Ferguson, TB Jr, Williams, DO, Harrington, RA, Stone, GW, Rosenberg, Y, ISCHEMIA Research Group

Background: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.

Methods: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.

Results: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).

Conclusions: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Keywords 
coronary artery disease cardiac ischemia cardiac interventions

The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application

Author/s: 
Lauer, S.A., Grantz, K.A, Bi, Q, Jones, F.K., Zheng, Q., Meredith, H.R., Azman, A.S., Reich, N.G., Lessler, J.

Abstract

Background:

A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in China in December 2019. There is limited support for many of its key epidemiologic features, including the incubation period for clinical disease (coronavirus disease 2019 [COVID-19]), which has important implications for surveillance and control activities.

Objective:

To estimate the length of the incubation period of COVID-19 and describe its public health implications.

Design:

Pooled analysis of confirmed COVID-19 cases reported between 4 January 2020 and 24 February 2020.

Setting:

News reports and press releases from 50 provinces, regions, and countries outside Wuhan, Hubei province, China.

Participants:

Persons with confirmed SARS-CoV-2 infection outside Hubei province, China.

Measurements:

Patient demographic characteristics and dates and times of possible exposure, symptom onset, fever onset, and hospitalization.

Results:

There were 181 confirmed cases with identifiable exposure and symptom onset windows to estimate the incubation period of COVID-19. The median incubation period was estimated to be 5.1 days (95% CI, 4.5 to 5.8 days), and 97.5% of those who develop symptoms will do so within 11.5 days (CI, 8.2 to 15.6 days) of infection. These estimates imply that, under conservative assumptions, 101 out of every 10 000 cases (99th percentile, 482) will develop symptoms after 14 days of active monitoring or quarantine.

Limitation:

Publicly reported cases may overrepresent severe cases, the incubation period for which may differ from that of mild cases.

Conclusion:

This work provides additional evidence for a median incubation period for COVID-19 of approximately 5 days, similar to SARS. Our results support current proposals for the length of quarantine or active monitoring of persons potentially exposed to SARS-CoV-2, although longer monitoring periods might be justified in extreme cases.

Primary Funding Source:

U.S. Centers for Disease Control and Prevention, National Institute of Allergy and Infectious Diseases, National Institute of General Medical Sciences, and Alexander von Humboldt Foundation.

In December 2019, a cluster of severe pneumonia cases of unknown cause was reported in Wuhan, Hubei province, China. The initial cluster was epidemiologically linked to a seafood wholesale market in Wuhan, although many of the initial 41 cases were later reported to have no known exposure to the market (1). A novel strain of coronavirus belonging to the same family of viruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as the 4 human coronaviruses associated with the common cold, was subsequently isolated from lower respiratory tract samples of 4 cases on 7 January 2020 (2). Infection with the virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can be asymptomatic or can result in mild to severe symptomatic disease (coronavirus disease 2019 [COVID-19]) (3). On 30 January 2020, the World Health Organization declared that the SARS-CoV-2 outbreak constituted a Public Health Emergency of International Concern, and more than 80 000 confirmed cases had been reported worldwide as of 28 February 2020 (4, 5). On 31 January 2020, the U.S. Centers for Disease Control and Prevention announced that all citizens returning from Hubei province, China, would be subject to mandatory quarantine for up to 14 days (6).

Our current understanding of the incubation period for COVID-19 is limited. An early analysis based on 88 confirmed cases in Chinese provinces outside Wuhan, using data on known travel to and from Wuhan to estimate the exposure interval, indicated a mean incubation period of 6.4 days (95% CI, 5.6 to 7.7 days), with a range of 2.1 to 11.1 days (7). Another analysis based on 158 confirmed cases outside Wuhan estimated a median incubation period of 5.0 days (CI, 4.4 to 5.6 days), with a range of 2 to 14 days (8). These estimates are generally consistent with estimates from 10 confirmed cases in China (mean incubation period, 5.2 days [CI, 4.1 to 7.0 days] [9]) and from clinical reports of a familial cluster of COVID-19 in which symptom onset occurred 3 to 6 days after assumed exposure in Wuhan (1). These estimates of the incubation period of SARS-CoV-2 are also in line with those of other known human coronaviruses, including SARS (mean, 5 days; range, 2 to 14 days [10]), MERS (mean, 5 to 7 days; range, 2 to 14 days [11]), and non-SARS human coronavirus (mean, 3 days; range, 2 to 5 days [12]).

The incubation period can inform several important public health activities for infectious diseases, including active monitoring, surveillance, control, and modeling. Active monitoring requires potentially exposed persons to contact local health authorities to report their health status every day. Understanding the length of active monitoring needed to limit the risk for missing SARS-CoV-2 infections is necessary for health departments to effectively use limited resources. In this article, we provide estimates of the incubation period of COVID-19 and the number of symptomatic infections missed under different active monitoring scenarios.

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