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Buprenorphine Dose and Time to Discontinuation Among Patients With Opioid Use Disorder in the Era of Fentanyl

Author/s: 
Chambers, Laura C., Hallowell, benjamin D., Zullo, Andrew R.

Question: Are higher doses of buprenorphine treatment for opioid use disorder associated with improved retention in treatment when use of fentanyl (vs heroin) is more prevalent?

Findings: In this cohort study of 6499 patients initiating buprenorphine treatment between 2016 and 2020, those prescribed the recommended daily dose (16 mg) were at significantly greater risk of treatment discontinuation within 180 days than those prescribed a higher dose (24 mg).

Meaning: The results of this study suggest that the value of higher buprenorphine doses than currently recommended needs to be considered for improving retention in treatment.

Keywords 
cohort study Opiod use disorder fentanyl

Dynamics of Naturally-Acquired Immunity Against SARS-CoV-2 in Children and Adolescents

Author/s: 
Patalon, T., Saciuk, Y., Perez, G., Peretz, A., Ben-Tov, A., Gazit, S.

Background
To evaluate the duration of protection against reinfection conferred by a previous SARS-CoV-2 infection in children and adolescents.
Methods
We applied two complementary approaches: a matched test-negative, case-control design and a retrospective cohort design. 458,959 unvaccinated individuals aged 5-18 years were included. Analyses focused on July 1 to December 13, 2021, a period of Delta variant dominance in Israel. We evaluated three SARS-CoV-2-related outcomes: documented PCR confirmed infection or reinfection, symptomatic infection or reinfection, and SARS-CoV-2-related hospitalization or death.
Findings
Overall, children and adolescents who were previously infected acquired durable protection against reinfection with SARS-CoV-2 for at least 18 months. Importantly, no SARS-CoV-2-related deaths were recorded in either the SARS-CoV-2 naïve group or the previously infected group. Effectiveness of naturally-acquired immunity against a recurrent infection reached 89.2% (95% CI: 84.7%-92.4%) three to six months after first infection, mildly declining to 82.5% (95% CI, 79.1%-85.3%) 9-12 months after infection, with a slight non-significant waning trend up to 18 months after infection. Additionally, we found that ages 5-11 years exhibited no significant waning of naturally acquired protection throughout the outcome period, whereas waning protection in the 12-18 year-old age group was more prominent, but still mild.
Interpretation
Children and adolescents who were previously infected with SARS-CoV-2 remain protected to a high degree for 18 months. Further research is needed to examine naturally-acquired immunity against Omicron and newer emerging variants.

Keywords 
COVID-19 SARS-CoV-2 waning immunity naturally aquired immunity infection-induced immunity adolescents

Normal pressure hydrocephalus treated with ventriculoperitoneal shunt

Author/s: 
Fereshtehnejad, S., Nicholls, M., Huang, S., Akter, R.

Normal pressure hydrocephalus is a form of adult hydrocephalus with ventriculomegaly in the absence of any structural blockage of the cerebrospinal fluid circulation.

Normal pressure hydrocephalus is a partially reversible cause of dementia, manifesting with a triad of cognitive impairment, gait disturbance and urinary incontinence.

A detailed cognitive assessment, neurologic examination and brain imaging is necessary to exclude alternative causes and confirm the diagnosis.

High-volume lumbar puncture with pre- and postprocedure gait assessment is recommended as a confirmatory test before a decision is made regarding therapeutic interventions such as shunting.

Keywords 
Hydrocephalus normal pressure neurology brain imaging ventriculoperitoneal shunt

Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel

Author/s: 
Mevorach, D., Anis, E., Cedar, N., Bromberg, M., Haas, E. J., Nadir, E., Olsha-Castell, S., Arad, D., Hasin, T., Levi, N., Asleh, R., Amir, O., Meir, K., Cohen, D., Dichtiar, R., Novick, D., Hershkovitz, Y., Dagan, R., Leitersdorf, I., Ben-Ami, R., Miskin, I., Saliba, W., Muhsen, K., Levi, Y., Green, M. S., Beinan-Boker, L., Alroy-Preis, S.

Background: Approximately 5.1 million Israelis had been fully immunized against coronavirus disease 2019 (Covid-19) after receiving two doses of the BNT162b2 messenger RNA vaccine (Pfizer-BioNTech) by May 31, 2021. After early reports of myocarditis during adverse events monitoring, the Israeli Ministry of Health initiated active surveillance.

Methods: We retrospectively reviewed data obtained from December 20, 2020, to May 31, 2021, regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons.

Results: Among 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal. The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20). The rate ratio 30 days after the second vaccine dose in fully vaccinated recipients, as compared with unvaccinated persons, was 2.35 (95% CI, 1.10 to 5.02); the rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83), with a ratio of 1 in 6637.

Conclusions: The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.

Keywords 
myocarditis Coronovirus COVID-19 Immunization vaccine

Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19

Author/s: 
Taquet, M., Dercon, Q., Luciano, S., Geddes, J. R., Husain, M., Harrison, P. J.

Background
Long-COVID refers to a variety of symptoms affecting different organs reported by people following Coronavirus Disease 2019 (COVID-19) infection. To date, there have been no robust estimates of the incidence and co-occurrence of long-COVID features, their relationship to age, sex, or severity of infection, and the extent to which they are specific to COVID-19. The aim of this study is to address these issues.

Methods and findings
We conducted a retrospective cohort study based on linked electronic health records (EHRs) data from 81 million patients including 273,618 COVID-19 survivors. The incidence and co-occurrence within 6 months and in the 3 to 6 months after COVID-19 diagnosis were calculated for 9 core features of long-COVID (breathing difficulties/breathlessness, fatigue/malaise, chest/throat pain, headache, abdominal symptoms, myalgia, other pain, cognitive symptoms, and anxiety/depression). Their co-occurrence network was also analyzed. Comparison with a propensity score–matched cohort of patients diagnosed with influenza during the same time period was achieved using Kaplan–Meier analysis and the Cox proportional hazard model. The incidence of atopic dermatitis was used as a negative control.

Among COVID-19 survivors (mean [SD] age: 46.3 [19.8], 55.6% female), 57.00% had one or more long-COVID feature recorded during the whole 6-month period (i.e., including the acute phase), and 36.55% between 3 and 6 months. The incidence of each feature was: abnormal breathing (18.71% in the 1- to 180-day period; 7.94% in the 90- to180-day period), fatigue/malaise (12.82%; 5.87%), chest/throat pain (12.60%; 5.71%), headache (8.67%; 4.63%), other pain (11.60%; 7.19%), abdominal symptoms (15.58%; 8.29%), myalgia (3.24%; 1.54%), cognitive symptoms (7.88%; 3.95%), and anxiety/depression (22.82%; 15.49%). All 9 features were more frequently reported after COVID-19 than after influenza (with an overall excess incidence of 16.60% and hazard ratios between 1.44 and 2.04, all p < 0.001), co-occurred more commonly, and formed a more interconnected network. Significant differences in incidence and co-occurrence were associated with sex, age, and illness severity. Besides the limitations inherent to EHR data, limitations of this study include that (i) the findings do not generalize to patients who have had COVID-19 but were not diagnosed, nor to patients who do not seek or receive medical attention when experiencing symptoms of long-COVID; (ii) the findings say nothing about the persistence of the clinical features; and (iii) the difference between cohorts might be affected by one cohort seeking or receiving more medical attention for their symptoms.

Conclusions
Long-COVID clinical features occurred and co-occurred frequently and showed some specificity to COVID-19, though they were also observed after influenza. Different long-COVID clinical profiles were observed based on demographics and illness severity.

Author summary
Why was this study done?
Long-COVID has been described in recent studies. But we do not know the risk of developing features of this condition and how it is affected by factors such as age, sex, or severity of infection.
We do not know if the risk of having features of long-COVID is more likely after Coronavirus Disease 2019 (COVID-19) than after influenza.
We do not know about the extent to which different features of long-COVID co-occur.
What did the researchers do and find?
This research used data from electronic health records of 273,618 patients diagnosed with COVID-19 and estimated the risk of having long-COVID features in the 6 months after a diagnosis of COVID-19. It compared the risk of long-COVID features in different groups within the population and also compared the risk to that after influenza.
The research found that over 1 in 3 patients had one or more features of long-COVID recorded between 3 and 6 months after a diagnosis of COVID-19. This was significantly higher than after influenza.
For 2 in 5 of the patients who had long-COVID features in the 3- to 6-month period, they had no record of any such feature in the previous 3 months.
The risk of long-COVID features was higher in patients who had more severe COVID-19 illness, and slightly higher among females and young adults. White and non-white patients were equally affected.
What do these findings mean?
Knowing the risk of long-COVID features helps in planning the relevant healthcare service provision.
The fact that the risk is higher after COVID-19 than after influenza suggests that their origin might, in part, directly involve infection with SARS-CoV-2 and is not just a general consequence of viral infection. This might help in developing effective treatments against long-COVID.
The findings in the subgroups, and the fact that the majority of patients who have features of long-COVID in the 3- to 6-month period already had symptoms in the first 3 months, may help in identifying those at greatest risk.

Do carotid artery calcifications seen on radiographs predict stenosis in asymptomatic adults?

Author/s: 
Cowdrey, D., Hahn, T. W., Vellardita, L.

EVIDENCE-BASED ANSWER:
NOT VERY WELL. IN ASYMPTOMATIC PATIENTS, CAROTID ARTERY CALCIFICATION SEEN ON RADIOGRAPH HAS A POSITIVE PREDICTIVE VALUE OF 70% AND A NEGATIVE PREDICTIVE VALUE OF 75% FOR CAROTID ARTERY STENOSIS (STRENGTH OF RECOMMENDATION [SOR]: B, SYSTEMATIC REVIEW OF OBSERVATIONAL STUDIES WITH HETEROGENEOUS RESULTS AND A RETROSPECTIVE COHORT STUDY). CAROTID CALCIFICATIONS ON RADIOGRAPHS MAY BE MORE PREDICTIVE OF CAROTID STENOSIS IN PEOPLE WITH ATHEROSCLEROTIC RISK FACTORS (SOR: C, CROSS-SECTIONAL STUDY). HARMS OUTWEIGH BENEFITS IN SCREENING FOR CAROTID ARTERY STENOSIS IN ASYMPTOMATIC ADULTS (SOR: B, MULTIPLE COHORT STUDIES); THEREFORE, INCIDENTAL RADIOGRAPHIC CAROTID ARTERY CALCIFICATIONS IN ASYMPTOMATIC PATIENTS SHOULD NOT PROMPT FURTHER TESTING.

A predictive equation to guide vitamin D replacement dose in patients

Author/s: 
Singh, G., Bonham, A. J.

Background: Vitamin D is essential for bone health and probably the health of most nonskeletal tissues. Vitamin D deficiency is widespread, and recommended doses are usually inadequate to maintain healthy levels. We conducted a retrospective observational study to determine whether the recommended doses of vitamin D are adequate to correct deficiency and maintain normal levels in a population seeking health care. We also sought to develop a predictive equation for replacement doses of vitamin D.

Methods: We reviewed the response to vitamin D supplementation in 1327 patients and 3885 episodes of vitamin D replacement and attempted to discern factors affecting the response to vitamin D replacement by conducting multiple regression analyses.

Results: For the whole population, average daily dose resulting in any increase in serum 25-hydroxyvitamin D level was 4707 IU/day; corresponding values for ambulatory and nursing home patients were 4229 and 6103 IU/day, respectively. Significant factors affecting the change in serum concentrations of 25-hydroxyvitamin D, in addition to the dose administered, are (1) starting serum concentration of 25-hydroxyvitamin D, (2) body mass index (BMI), (3) age, and (f) serum albumin concentration. The following equation predicts the dose of vitamin D needed (in international units per day) to affect a given change in serum concentrations of 25-hydroxyvitamin D: Dose = [(8.52 - Desired change in serum 25-hydroxyvitamin D level) + (0.074 × Age) - (0.20 × BMI) + (1.74 × Albumin concentration) - (0.62 × Starting serum 25-hydroxyvitamin D concentration)]/(-0.002). Analysis of the dose responses among 3 racial groups-white, black, and others-did not reveal clinically meaningful differences between the races. The main limitation of the study is its retrospective observational nature; however, that is also its strength in that we assessed the circumstances seen in usual health care setting.

Conclusions: The recommended daily allowance for vitamin D is grossly inadequate for correcting low serum concentrations of 25-hydroxyvitamin D in many adult patients. About 5000 IU vitamin D3/day is usually needed to correct deficiency, and the maintenance dose should be ≥2000 IU/day. The required dose may be calculated from the predictive equations specific for ambulatory and nursing home patients.

Mortality and concurrent use of opioids and hypnotics in older patients: A retrospective cohort study

Author/s: 
W. A., Chung, C. P., Murray, K. T., Malow, B. A., Daugherty, J. R., Stein, C. M.

Background: Benzodiazepine hypnotics and the related nonbenzodiazepine hypnotics (z-drugs) are among the most frequently prescribed medications for older adults. Both can depress respiration, which could have fatal cardiorespiratory effects, particularly among patients with concurrent opioid use. Trazodone, frequently prescribed in low doses for insomnia, has minimal respiratory effects, and, consequently, may be a safer hypnotic for older patients. Thus, for patients beginning treatment with benzodiazepine hypnotics or z-drugs, we compared deaths during periods of current hypnotic use, without or with concurrent opioids, to those for comparable patients receiving trazodone in doses up to 100 mg.

Methods and findings: The retrospective cohort study in the United States included 400,924 Medicare beneficiaries 65 years of age or older without severe illness or evidence of substance use disorder initiating study hypnotic therapy from January 2014 through September 2015. Study endpoints were out-of-hospital (primary) and total mortality. Hazard ratios (HRs) were adjusted for demographic characteristics, psychiatric and neurologic disorders, cardiovascular and renal conditions, respiratory diseases, pain-related diagnoses and medications, measures of frailty, and medical care utilization in a time-dependent propensity score-stratified analysis. Patients without concurrent opioids had 32,388 person-years of current use, 260 (8.0/1,000 person-years) out-of-hospital and 418 (12.9/1,000) total deaths for benzodiazepines; 26,497 person-years,150 (5.7/1,000) out-of-hospital and 227 (8.6/1,000) total deaths for z-drugs; and 16,177 person-years,156 (9.6/1,000) out-of-hospital and 256 (15.8/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (respective HRs: 0.99 [95% confidence interval, 0.81 to 1.22, p = 0.954] and 0.95 [0.82 to 1.14, p = 0.513] and z-drugs (HRs: 0.96 [0.76 to 1.23], p = 0.767 and 0.87 [0.72 to 1.05], p = 0.153) did not differ significantly from that for trazodone. Patients with concurrent opioids had 4,278 person-years of current use, 90 (21.0/1,000) out-of-hospital and 127 (29.7/1,000) total deaths for benzodiazepines; 3,541 person-years, 40 (11.3/1,000) out-of-hospital and 64 (18.1/1,000) total deaths for z-drugs; and 2,347 person-years, 19 (8.1/1,000) out-of-hospital and 36 (15.3/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (HRs: 3.02 [1.83 to 4.97], p < 0.001 and 2.21 [1.52 to 3.20], p < 0.001) and z-drugs (HRs: 1.98 [1.14 to 3.44], p = 0.015 and 1.65 [1.09 to 2.49], p = 0.018) were significantly increased relative to trazodone; findings were similar with exclusion of overdose deaths or restriction to those with cardiovascular causes. Limitations included composition of the study cohort and potential confounding by unmeasured variables.

Conclusions: In US Medicare beneficiaries 65 years of age or older without concurrent opioids who initiated treatment with benzodiazepine hypnotics, z-drugs, or low-dose trazodone, study hypnotics were not associated with mortality. With concurrent opioids, benzodiazepines and z-drugs were associated with increased out-of-hospital and total mortality. These findings indicate that the dangers of benzodiazepine-opioid coadministration go beyond the documented association with overdose death and suggest that in combination with opioids, the z-drugs may be more hazardous than previously thought.

Keywords 
opioids Hypnotics cohort study mortality Drug Overdose

Kinetics of viral clearance and antibody production across age groups in SARS-CoV-2 infected children

Author/s: 
Bahar, Burak, Jacquot, Cyril, Mo, Yunchuan D., DeBiasi, Roberta L., Campos, Joseph, Delaney, Meghan

Abstract

Objectives: To improve understanding of transition from viral infection to viral clearance, and antibody response in pediatric patients with SARS-CoV-2 infection.

Study design: This retrospective analysis of children tested for SARS-CoV-2 by RT-PCR and IgG antibody at a quaternary-care, free-standing pediatric hospital between March 13, 2020 to June 21, 2020 included 6369 patients who underwent PCR testing and 215 patients who underwent antibody testing. During the initial study period, testing focused primarily on symptomatic children; the later study period included asymptomatic patients who underwent testing as preadmission or preprocedural screening. We report the proportion of positive and negative tests, time to viral clearance, and time to seropositivity.

Results: The rate of positivity varied over time due to viral circulation in the community and transition from targeted testing of symptomatic patients to more universal screening of hospitalized patients. Median duration of viral shedding (RT-PCR positivity) was 19.5 days and time from RT-PCR positivity to negativity was 25 days. Of note, patients aged 6 through 15 years demonstrated a longer time of RT-PCR positivity to negativity, compared with patients aged 16 through 22 years (median=32 versus 18 days, P = .015). Median time to seropositivity, by chemiluminescent testing, from RT-PCR positivity was 18 days while median time to reach adequate levels of neutralizing antibodies (defined as comparable to 160 titer by plaque reduction neutralization testing) was 36 days.

Conclusions: The majority of patients demonstrated a prolonged period of viral shedding after infection with SARS CoV-2. It is unknown whether this correlates with persistent infectivity. Only 17 of 33 patients demonstrated adequate neutralizing antibodies during the timeframe of specimen collection. It remains unknown if IgG antibody against spike structured proteins correlates with immunity, and how long antibodies and potential protection persist.

Copyright © 2020. Published by Elsevier Inc.

Association Between Age and Complications After Outpatient Colonoscopy

Author/s: 
Causada-Calo, N., Bishay, K., Albashir, S., Mazroui, A.A., Armstrong, D.

Abstract

Importance: There are insufficient data describing the incidence and risk factors of postcolonoscopy complications in older individuals.

Objective: To assess the association between older age (≥75 years) and the risk of postcolonoscopy complications.

Design, setting, and participants: This population-based retrospective cohort study included adults (≥50 years) undergoing outpatient colonoscopy between April 2008 and September 2017, identified from Ontario administrative databases. Individuals with inflammatory bowel disease and hereditary colorectal cancer syndromes were excluded. The study population was subdivided into a colorectal cancer screening-eligible cohort (patients aged 50-74 years) and an older cohort (patients aged ≥75 years). The statistical analysis was conducted from December 2018 to September 2019.

Exposures: Older age (≥75 years).

Main outcomes and measures: The primary outcome was postcolonoscopy complications, defined as the composite of hospitalization or emergency department visits in the 30-day period after the outpatient colonoscopy. Secondary outcomes included incidence of surgically treated colorectal cancer and all-cause mortality at 30 days. Independent variables associated with postcolonoscopy complications were also assessed.

Results: The study sample included 38 069 patients; the mean (SD) age was 65.2 (10.1) years, there were 19 037 women (50.0%), and 27 831 patients (73.1%) underwent a first colonoscopy. The cumulative incidence of complications was 3.4% (1310 patients) in the overall population, and it was higher in individuals aged 75 years or older (515 of 7627 patients [6.8%]) than in screening-eligible cohort (795 of 30 443 patients [2.6%]) (P < .001). Independent risk factors for postcolonoscopy complications were age 75 years or older (odds ratio [OR], 2.3; 95% CI, 2.0-2.6), anemia (OR, 1.4; 95% CI, 1.2-1.7), cardiac arrhythmia (OR, 1.7; 95% CI, 1.2-2.2), congestive heart failure (OR, 3.4; 95% CI, 2.5-4.6), hypertension (OR, 1.2; 95% CI, 1.0-1.5), chronic kidney disease (OR, 1.8; 95% CI, 1.1-3.0), liver disease (OR, 4.7; 95% CI, 3.5-6.5), smoking history (OR, 3.2; 95% CI, 2.4-4.3), and obesity (OR, 2.3; 95% CI, 1.2-4.2). The number of previous colonoscopies was associated with a lower risk of complications (OR, 0.9; 95% CI, 0.7-1.0). The incidence of surgically treated colorectal cancer was higher in the older cohort than the screening-eligible cohort (119 patients [1.6%] vs 144 patients [0.5%]; P < .001). All-cause mortality rates were 0.1% overall (39 patients) and 0.1% (19 patients) for individuals aged 50 to 74 years and 0.2% (20 patients) for those aged 75 years and older (P < .001).

Conclusions and relevance: In this population-based cohort study of individuals living in southern Ontario, age of 75 years and older was associated with a higher risk of 30-day postprocedure complications after outpatient colonoscopy. These findings suggest that the decision to perform a colonoscopy should be carefully considered in patients older than 75 years, especially in the presence of comorbidities. Further studies are needed to better understand the benefits of invasive procedures as opposed to less invasive approaches for colorectal cancer screening and surveillance among older patients.

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