Risk for Reinfection After SARS-CoV-2: A Living, Rapid Review for American College of Physicians Practice Points on the Role of the Antibody Response in Conferring Immunity Following SARS-CoV-2 Infection.

BACKGROUND: The strength and duration of immunity from infection with SARS-CoV-2 are important for public health planning and clinical practice. PURPOSE: To synthesize evidence on protection against reinfection after SARS-CoV-2 infection. DATA SOURCES: MEDLINE (Ovid), the World Health Organization global literature database, ClinicalTrials.gov, COVID19reviews.org, and reference lists. STUDY SELECTION: Longitudinal studies that compared the risk for reinfection after SARS-CoV-2 infection versus infection risk in individuals with no prior infection. DATA EXTRACTION: Two investigators sequentially extracted study data and rated quality. DATA SYNTHESIS: Across 18 eligible studies, reinfection risk ranged from 0% to 2.2%. In persons with recent SARS-CoV-2 infection compared with unvaccinated, previously uninfected individuals, 80% to 98% of symptomatic infections with wild-type or Alpha variants were prevented (high strength of evidence). In the meta-analysis, previous infection reduced risk for reinfection by 87% (95% CI, 84% to 90%), equaling 4.3 fewer infections per 100 persons in both the general population (risk difference, -0.043 [CI, -0.071 to -0.015]) and health care workers (risk difference, -0.043 [CI, -0.069 to -0.016]), and 26.6 fewer infections per 100 persons in care facilities (risk difference, -0.266 [CI, -0.449 to -0.083]). Protection remained above 80% for at least 7 months, but no study followed patients after the emergence of the Delta or Omicron variant. Results for the elderly were conflicting. LIMITATION: Methods to ascertain and diagnose infections varied. CONCLUSION: Before the emergence of the Delta and Omicron variants, persons with recent infection had strong protection against symptomatic reinfections for 7 months compared with unvaccinated, previously uninfected individuals. Protection in immunocompromised persons, racial and ethnic subgroups, and asymptomatic index case patients is unclear. The durability of protection in the setting of the Delta and Omicron variants is unknown. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42020207098).

Antibody Response After SARS-CoV-2 Infection and Implications for Immunity : A Rapid Living Review.

BACKGROUND: The clinical significance of the antibody response after SARS-CoV-2 infection remains unclear. PURPOSE: To synthesize evidence on the prevalence, levels, and durability of detectable antibodies after SARS-CoV-2 infection and whether antibodies to SARS-CoV-2 confer natural immunity. DATA SOURCES: MEDLINE (Ovid), Embase, CINAHL, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, World Health Organization global literature database, and Covid19reviews.org from 1 January through 15 December 2020, limited to peer-reviewed publications available in English. STUDY SELECTION: Primary studies characterizing the prevalence, levels, and duration of antibodies in adults with SARS-CoV-2 infection confirmed by reverse transcriptase polymerase chain reaction (RT-PCR); reinfection incidence; and unintended consequences of antibody testing. DATA EXTRACTION: Two investigators sequentially extracted study data and rated quality. DATA SYNTHESIS: Moderate-strength evidence suggests that most adults develop detectable levels of IgM and IgG antibodies after infection with SARS-CoV-2 and that IgG levels peak approximately 25 days after symptom onset and may remain detectable for at least 120 days. Moderate-strength evidence suggests that IgM levels peak at approximately 20 days and then decline. Low-strength evidence suggests that most adults generate neutralizing antibodies, which may persist for several months like IgG. Low-strength evidence also suggests that older age, greater disease severity, and presence of symptoms may be associated with higher antibody levels. Some adults do not develop antibodies after SARS-CoV-2 infection for reasons that are unclear. LIMITATIONS: Most studies were small and had methodological limitations; studies used immunoassays of variable accuracy. CONCLUSION: Most adults with SARS-CoV-2 infection confirmed by RT-PCR develop antibodies. Levels of IgM peak early in the disease course and then decline, whereas IgG peaks later and may remain detectable for at least 120 days. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42020207098).

Biological measures and diagnostic tools for Gulf War Illness - A systematic review.

AIMS: Gulf War Illness (GWI) is a chronic multisymptom illness with debated etiology and pathophysiology. This systematic review catalogues studies of validated biological tests for diagnosing GWI and of associations between biological measures and GWI for their promise as biomarkers. MAIN METHODS: We searched multiple sources through February 2020 for studies of diagnostic tests of GWI and of associations between biological measures and GWI. We abstracted data on study design, demographics, and outcomes. We assessed the risk of bias of included studies. KEY FINDINGS: We did not identify any studies validating tests of biomarkers that distinguish cases of GWI from non-cases. We included the best-fitting studies, 32 completed and 24 ongoing or unpublished studies, of associations between GWI and biological measures. The less well-fitting studies (n = 77) were included in a Supplementary Table. Most studies were of the central nervous and immune systems and indicated a significant association of the biological measure with GWI case status. Biological measures were heterogeneous across studies. SIGNIFICANCE: Our review indicates that there are no existing validated biological tests to determine GWI case status. Many studies have assessed the potential association between a variety of biological measures and GWI, the majority of which pertain to the immune and central nervous systems. More importantly, while most studies indicated a significant association between biological measures and GWI case status, the biological measures across studies were extremely heterogeneous. Due to the heterogeneity, the focus of the review is to map out what has been examined, rather than synthesize information.

Retention Strategies for Medications for Opioid Use Disorder in Adults: A Rapid Evidence Review.

OBJECTIVES: Although medications for opioid use disorder (MOUD) save lives, treatment retention remains challenging. Identification of interventions to improve MOUD retention is of interest to policymakers and researchers. On behalf of the Agency for Healthcare Research and Quality, we conducted a rapid evidence review on interventions to improve MOUD retention. METHODS: We searched MEDLINE and the Cochrane Library from February 2009 through August 2019 for systematic reviews and randomized trials of care settings, services, logistical support, contingency management, health information technology (IT), extended-release (XR) formulations, and psychosocial interventions that assessed retention at least 3 months. RESULTS: Two systematic reviews and 39 primary studies were included; most did not focus on retention as the primary outcome. Initiating MOUD in soon-to-be-released incarcerated people improved retention following release. Contingency management may improve retention using antagonist but not agonist MOUD. Retention with interventions integrating medical, psychiatric, social services, or IT did not differ from in-person treatment-as-usual approaches. Retention was comparable with XR- compared to daily buprenorphine formulations and conflicting with XR-naltrexone monthly injection compared to daily buprenorphine. Most psychosocial interventions did not improve retention. DISCUSSION: Consistent but sparse evidence supports criminal justice prerelease MOUD initiation, and contingency management interventions for antagonist MOUD. Integrating MOUD with medical, psychiatric, social services, delivering through IT, or administering via XR-MOUD formulations did not worsen retention. Fewer than half of the studies we identified focused on retention as a primary outcome. Studies used different measures of retention, making it difficult to compare effectiveness. Additional inquiry into the causes of low retention would inform future interventions.Registration: PROSPERO: CRD42019134739.

The Role of Dopamine in Value-Based Attentional Orienting.

Reward learning gives rise to strong attentional biases. Stimuli previously associated with reward automatically capture visual attention regardless of intention. Dopamine signaling within the ventral striatum plays an important role in reward learning, representing the expected reward initiated by a cue. How dopamine and the striatum may be involved in maintaining behaviors that have been shaped by reward learning, even after reward expectancies have changed, is less well understood. Nonspecific measures of brain activity have implicated the striatum in value-based attention. However, the neurochemical mechanisms underlying the attentional priority of learned reward cues remain unexplored. Here, we investigated the contribution of dopamine to value-based attention using positron emission tomography (PET) with [(11)C]raclopride. We show that, in the explicit absence of reward, the magnitude of attentional capture by previously reward-associated but currently task-irrelevant distractors is correlated across individuals with changes in available D2/D3 dopamine receptors (presumably due to intrasynaptic dopamine) linked to distractor processing within the right caudate and posterior putamen. Our findings provide direct evidence linking dopamine signaling within the striatum to the involuntary orienting of attention, and specifically to the attention-grabbing quality of learned reward cues. These findings also shed light on the neurochemical basis of individual susceptibility to value-driven attentional capture, which is known to play a role in addiction. More broadly, the present study highlights the value and feasibility of using PET to relate changes in the release of a neurotransmitter to learning-dependent changes in healthy adults.

Advances in CNS Imaging Agents: Focus on PET and SPECT Tracers in Experimental and Clinical Use.

The physiological functioning of the brain is not well-known in current day medicine and the pathologies of many neuropsychiatric disorders are still not yet fully understood. With our aging population and better life expectancies, it has become imperative to find better biomarkers for disease progression as well as receptor target engagements. In the last decade, these major advances in the field of molecular CNS imaging have been made available with tools such as functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), single photon emission computed tomography (SPECT), and neuroreceptor-targeted positron emission tomography (PET). These tools have given researchers, pharmaceutical companies, and clinical physicians a better method of understanding CNS dysfunctions, and the ability to employ improved therapeutic agents. This review is intended to provide an update on brain imaging agents that are currently used in clinical and translational research toward treatment of CNS disorders. The review begins with amyloid and tau imaging, the former of which has at least three [(18)F] agents that have been recently approved and will soon be available for clinical use for specific indications in the USA and elsewhere. Other prevalent PET and SPECT neurotransmitter system agents, including those newly US FDA-approved imaging agents related to the dopaminergic system, are included. A review of both mature and potentially growing PET imaging agents, including those targeting serotonin and opiate receptor systems, is also provided.

PET imaging of high-affinity α4ß2 nicotinic acetylcholine receptors in humans with 18F-AZAN, a radioligand with optimal brain kinetics.

UNLABELLED: We evaluated (-)-2-(6-[(18)F]fluoro-2,3'-bipyridin-5'-yl)-7-methyl-7-aza-bicyclo[2.2.1]heptane ((18)F-AZAN), a novel radiotracer that binds to α4ß2 nicotinic acetylcholine receptors (α4ß2-nAChRs) and shows high specific binding and rapid and reversible kinetics in the baboon and human brain. METHODS: We tested safety tolerability and test-retest reliability (n = 5) and proposed initial quantification of (18)F-AZAN receptors in 3 healthy human subjects who had nicotine exposure and 9 who did not. We also present a receptor blocking study in a nicotine subject dosed with the α4ß2-nAChR-selective partial agonist varenicline. RESULTS: Radiation dosimetry PET/CT experiments indicated that most human organs received doses between 0.008 and 0.015 mSv/MBq, with an effective dose of approximately 0.014 mSv/MBq. The tracer rapidly entered the brain, and the peak was reached before 20 min, even for thalamus. Ninety-minute scans were sufficient for (18)F-AZAN to obtain the ratio at equilibrium of specifically bound radioligand to nondisplaceable radioligand in tissue (BPND) using plasma reference graphical analysis, which showed excellent reproducibility of BPND (test-retest variability < 10%) in the nAChR-rich brain regions. Regional plasma reference graphical analysis BP(ND) values exceeded 2 in the midbrain tegmental nuclei, lateral geniculate body, and thalamus for nonsmokers (n = 9) but were less than 1 in the nAChR-poor brain regions. There was a dramatic reduction of (18)F-AZAN brain uptake in smokers and varenicline-treated subjects. CONCLUSION: (18)F-AZAN is a highly specific, safe, and effective PET radioligand for human subjects that requires only 90 min of PET scanning to estimate high-affinity α4ß2-nAChR in the living human brain.

Determination of dopamine D2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjects.

RATIONALE: A positron emission tomography (PET) study of dopamine D2 receptor occupancy was conducted to support a rational dose selection for clinical efficacy studies with lurasidone, an atypical antipsychotic that was approved for the treatment of schizophrenia by the FDA in late 2010. OBJECTIVES: To determine the dopamine D2 receptor occupancy of lurasidone in the ventral striatum, putamen and caudate nucleus, and to characterize the relationship between lurasidone serum concentration and D2 receptor occupancy. METHODS: A single oral dose of lurasidone (10, 20, 40, 60, or 80 mg) was administered sequentially to healthy male subjects (n = 4 in each cohort). Two PET scans were performed. For each scan, 20 mCi of [¹¹C]raclopride was administered intravenously as a bolus injection, followed immediately by 90 min of PET scan acquisitions. RESULTS: The D2 receptor occupancy levels were 41-43% for 10 mg, 51-55% for 20 mg, 63-67% for 40 mg, 77-84% for 60 mg, and 73-79% for 80 mg of lurasidone. The relationship between D2 receptor occupancy and the mean serum lurasidone concentration during the PET scan (C PET) was similar for the putamen, caudate nucleus, and ventral striatum regions. Mean D2 receptor occupancy levels correlated well with average peak serum concentration of lurasidone. CONCLUSIONS: In healthy volunteers, single doses of lurasidone 40-80 mg resulted in D2 receptor occupancy levels of >60%, a level of receptor occupancy previously associated with clinical response for atypical antipsychotics.