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Introduction Perflutren microbubble/microsphere ultrasound contrast agents have a black-box warning based on case reports of serious cardiopulmonary events. There have been several subsequent observational safety studies. Large spontaneous reporting databases may help detect/refine signals of rare adverse events that elude other data sources/study designs. Objective The objective of this study was to supplement existing knowledge of the reported safety of perflutren using statistical analysis of spontaneous reports. Methods We analyzed information from the US Food and Drug Administration Adverse Event Reporting System using a disproportionality analysis. Analysis of overall reporting for perflutren was supplemented by subset (age, indication) analysis. A signal of disproportionate reporting (SDR) was defined as EB05 >2. Results Overall, 18/380 Preferred Terms and 1/83 Standardized Medical Queries had SDRs. Most were small (EB05 = 2–4). Back pain and flank pain were the largest SDRs followed by events compatible with signs/symptoms of hypersensitivity. The general pattern of SDRs in the subset analysis was consistent with the overall analysis. Almost all events with SDRs were literally or conceptually labeled. Except for chest pain (higher in the age <65 years subgroup) and back pain (higher in the age ≥65 years subgroup), there were no statistically significant differences between age subsets. Except for the Preferred Terms Pruritus and Urticaria and the narrow Standardized Medical Queries Ventricular tachyarrhythmia, Angioedema, Oropharyngeal allergic conditions, and Hypersensitivity (higher in the stress test subgroup), there were no statistically significant reporting differences between indication subsets. There were no SDRs associated with the major cardiovascular events of death, myocardial infarction/ischemia, angina, arrhythmias, or convulsions in any analysis. Conclusions Our combined signal detection/evaluation analysis did not identify SDRs of novel adverse events or major cardiovascular events associated with perflutren ultrasound contrast agents. The negative results for major cardiovascular events extend previous signal evaluation exercises supporting the relative cardiovascular safety of these agents.

Background Many illnesses demonstrate seasonal and geographic variations. Pharmacovigilance is unique among public health surveillance systems in terms of the clinical diversity of the events under surveillance. Since many pharmacovigilance signal detection methodologies are geared towards looking for increased frequency of spontaneous adverse drug event (ADE) reporting over variable time frames, seasonality of ADEs may have implications for signal detection. Objective The aim of this study was to investigate whether a set of illnesses that might be expected to display seasonality in general, did so when spontaneously reported as ADEs. Methods We performed our analysis with the publically available US FDA Adverse Event Reporting System (FAERS) data. We selected a convenience sample of events possibly triggered by seasonal factors (hypothermia, Raynaud’s phenomenon, photosensitivity reaction, heat exhaustion, heat stroke, and sunburn) and events for which previous literature experience suggests seasonality (anencephaly and interstitial lung disease). Our statistical procedures can be explained in terms of a simple physicogeometric setting: the unit circle divided into 6 (semiannual sinusoidal) or 12 (annual sinusoidal) arcs. When reporting frequencies (weights) are more or less evenly distributed across months, the center of mass of the circle would not be significantly displaced from the origin (0, 0). Distinct seasonal patterns will significantly displace the center of mass of the circle. Results Various patterns of seasonality were identified for some, but not all, events and region–event pairs. USA displayed the most instances of seasonality. Scandinavia did not display seasonality for any events. Seasonality was usually annual sinusoidal. Possible explanations for failure to observe seasonality are briefly considered. Conclusions Understanding seasonality of spontaneous ADE reporting may have public health policy and research implications and may mitigate false-positive and missed true-positive pharmacovigilance signals. More systematic study of seasonality of spontaneous ADE reporting, including additional events with more or less biological rationale for seasonality, is a logical extension of this analysis.

Introduction: There is an interest in methodologies to expeditiously detect credible signals of drug-induced pancreatitis. An example is the reported signal of pancreatitis with rasburicase emerging from a study [the ‘index publication’ (IP)] combining quantitative signal detection findings from a spontaneous reporting system (SRS) and electronic health records (EHRs). The signal was reportedly supported by a clinical review with a case series manuscript in progress. The reported signal is noteworthy, being initially classified as a false-positive finding for the chosen reference standard, but reclassified as a ‘clinically supported’ signal. Objective: This paper has dual objectives: to revisit the signal of rasburicase and acute pancreatitis and extend the original analysis via reexamination of its findings, in light of more contemporary data; and to motivate discussions on key issues in signal detection and evaluation, including recent findings from a major international pharmacovigilance research initiative. Methodology: We used the same methodology as the IP, including the same disproportionality analysis software/dataset for calculating observed to expected reporting frequencies (O/Es), Medical Dictionary for Regulatory Activities Preferred Term, and O/E metric/threshold combination defining a signal of disproportionate reporting. Baseline analysis results prompted supplementary analyses using alternative analytical choices. We performed a comprehensive literature search to identify additional published case reports of rasburicase and pancreatitis. Results: We could not replicate positive findings (e.g. a signal or statistic of disproportionate reporting) from the SRS data using the same algorithm, software, dataset and vendor specified in the IP. The reporting association was statistically highlighted in default and supplemental analysis when more sensitive forms of disproportionality analysis were used. Two of three reports in the FAERS database were assessed as likely duplicate reports. We did not identify any additional reports in the FAERS corresponding to the three cases identified in the IP using EHRs. We did not identify additional published reports of pancreatitis associated with rasburicase. Discussion: Our exercise stimulated interesting discussions of key points in signal detection and evaluation, including causality assessment, signal detection algorithm performance, pharmacovigilance terminology, duplicate reporting, mechanisms for communicating signals, the structure of the FAERs database, and recent results from a major international pharmacovigilance research initiative.

The SARS-CoV-2 pandemic poses the greatest global public health challenge in a century. Neutralizing antibody is a correlate of protection and data on kinetics of virus neutralizing antibody responses are needed. We tested 293 sera from an observational cohort of 195 reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infections collected from 0 to 209 days after onset of symptoms. Of 115 sera collected ≥61 days after onset of illness tested using plaque reduction neutralization (PRNT) assays, 99.1% remained seropositive for both 90% (PRNT 90 ) and 50% (PRNT 50 ) neutralization endpoints. We estimate that it takes at least 372, 416 and 133 days for PRNT 50 titres to drop to the detection limit of a titre of 1:10 for severe, mild and asymptomatic patients, respectively. At day 90 after onset of symptoms (or initial RT-PCR detection in asymptomatic infections), it took 69, 87 and 31 days for PRNT 50 antibody titres to decrease by half (T 1/2 ) in severe, mild and asymptomatic infections, respectively. Patients with severe disease had higher peak PRNT 90 and PRNT 50 antibody titres than patients with mild or asymptomatic infections. Age did not appear to compromise antibody responses, even after accounting for severity. We conclude that SARS-CoV-2 infection elicits robust neutralizing antibody titres in most individuals. Here, the authors perform plaque reduction neutralization (PRNT) assays quantitating SARS-CoV-2 specific neutralizing antibodies from 195 patients in different disease states and find that patients with severe disease exhibit higher peaks of neutralizing antibody titres than patients with mild or asymptomatic infections and that serum neutralizing antibody persists for over 6 months in most people.

SARS-CoV-2 infection of children leads to a mild illness and the immunological differences with adults are unclear. Here, we report SARS-CoV-2 specific T cell responses in infected adults and children and find that the acute and memory CD4 + T cell responses to structural SARS-CoV-2 proteins increase with age, whereas CD8 + T cell responses increase with time post-infection. Infected children have lower CD4 + and CD8 + T cell responses to SARS-CoV-2 structural and ORF1ab proteins when compared with infected adults, comparable T cell polyfunctionality and reduced CD4 + T cell effector memory. Compared with adults, children have lower levels of antibodies to β-coronaviruses, indicating differing baseline immunity. Total T follicular helper responses are increased, whilst monocyte numbers are reduced, indicating rapid adaptive co-ordination of the T and B cell responses and differing levels of inflammation. Therefore, reduced prior β-coronavirus immunity and reduced T cell activation in children might drive milder COVID-19 pathogenesis. Why children are generally less susceptible than adults to COVID-19 is unclear and has not extensively been examined longitudinally. Here the authors compare antibodies, cytokines and immune cell responses in adults and children over 6 months post-infection showing, among other things, a reduced CD4+ and CD8+ T cell response in children.

Background. Volunteer challenge studies have provided detailed data on viral shedding from the respiratory tract before and through the course of experimental influenza virus infection. There are no comparable quantitative data to our knowledge on naturally acquired infections. Methods. In a community-based study in Hong Kong in 2008, we followed up initially healthy individuals to quantify trends in viral shedding on the basis of cultures and reverse-transcription polymerase chain reaction (RT-PCR) through the course of illness associated with seasonal influenza A and B virus infection. Results. Trends in symptom scores more closely matched changes in molecular viral loads measured with RT-PCR for influenza A than for influenza B. For influenza A virus infections, the replicating viral loads determined with cultures decreased to undetectable levels earlier after illness onset than did molecular viral loads. Most viral shedding occurred during the first 2–3 days after illness onset, and we estimated that 1%–8% of infectiousness occurs prior to illness onset. Only 14% of infections with detectable shedding at RT-PCR were asymptomatic, and viral shedding was low in these cases. Conclusions. Our results suggest that “silent spreaders” (ie, individuals who are infectious while asymptomatic or presymptomatic) may be less important in the spread of influenza epidemics than previously thought.

Abstract Negative symptoms, particularly the motivation and pleasure (MAP) deficits, are associated with impaired social functioning in patients with schizophrenia (SCZ). However, previous studies seldom examined the role of the MAP on social functioning while accounting for the complex interplay between other psychopathology. This network analysis study examined the network structure and interrelationship between negative symptoms (at the “symptom-dimension” and “symptom-item” levels), other psychopathology and social functioning in a sample of 269 patients with SCZ. The psychopathological symptoms were assessed using the Clinical Assessment Interview for Negative Symptoms (CAINS) and the Positive and Negative Syndrome Scale (PANSS). Social functioning was evaluated using the Social and Occupational Functioning Assessment Scale (SOFAS). Centrality indices and relative importance of each node were estimated. The network structures between male and female participants were compared. Our resultant networks at both the “symptom-dimension” and the “symptom-item” levels suggested that the MAP factor/its individual items were closely related to social functioning in SCZ patients, after controlling for the complex interplay between other nodes. Relative importance analysis showed that MAP factor accounted for the largest proportion of variance of social functioning. This study is among the few which used network analysis and the CAINS to examine the interrelationship between negative symptoms and social functioning. Our findings supported the pivotal role of the MAP factor to determine SCZ patients’ social functioning, and as a potential intervention target for improving functional outcomes of SCZ.

The antibody response magnitude and kinetics may impact clinical severity, serological diagnosis and long-term protection of COVID-19, which may play a role in why children experience lower morbidity. We therefore tested samples from 122 children in Hong Kong with symptomatic ( n  = 78) and asymptomatic ( n  = 44) SARS-CoV-2 infections up to 200 days post infection, relative to 71 infected adults (symptomatic n  = 61, and asymptomatic n  = 10), and negative controls ( n  = 48). We assessed serum IgG antibodies to a 14-wide antigen panel of structural and accessory proteins by Luciferase Immuno-Precipitation System (LIPS) assay and circulating cytokines. Infected children have lower levels of Spike, Membrane, ORF3a, ORF7a, ORF7b antibodies, comparable ORF8 and elevated E-specific antibodies than adults. Combination of two unique antibody targets, ORF3d and ORF8, can accurately discriminate SARS-CoV-2 infection in children. Principal component analysis reveals distinct pediatric serological signatures, and the highest contribution to variance from adults are antibody responses to non-structural proteins ORF3d, NSP1, ORF3a and ORF8. From a diverse panel of cytokines that can modulate immune priming and relative inflammation, IL-8, MCP-1 and IL-6 correlate with the magnitude of pediatric antibody specificity and severity. Antibodies to SARS-CoV-2 internal proteins may become an important sero surveillance tool of infection with the roll-out of vaccines in the pediatric population. The antibody response of children to SARS-CoV-2 is less well studied than in adults. Here Hachim et al. show that children have reduced antibody levels to structural proteins and suggest that the predominance of antibody responses to non-structural proteins can be used to discriminate infection and vaccination.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis 1 – 5 . However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance 6 . In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment—which contributes to virologic failure, resistance generation and viral transmission—as well as of pre-exposure prophylaxis, leading to new infections 1 , 2 , 4 , 7 – 9 . Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence 10 . Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log 10 -transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV. The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.

Current genome-wide association studies (GWAS) for kidney function lack ancestral diversity, limiting the applicability to broader populations. The East-Asian population is especially under-represented, despite having the highest global burden of end-stage kidney disease. We conducted a meta-analysis of multiple GWASs ( n  = 244,952) on estimated glomerular filtration rate and a replication dataset ( n  = 27,058) from Taiwan and Japan. This study identified 111 lead SNPs in 97 genomic risk loci. Functional enrichment analyses revealed that variants associated with F12 gene and a missense mutation in ABCG2 may contribute to chronic kidney disease (CKD) through influencing inflammation, coagulation, and urate metabolism pathways. In independent cohorts from Taiwan ( n  = 25,345) and the United Kingdom ( n  = 260,245), polygenic risk scores (PRSs) for CKD significantly stratified the risk of CKD ( p  < 0.0001). Further research is required to evaluate the clinical effectiveness of PRS CKD in the early prevention of kidney disease. Here the authors present a large genetic study in East Asians that identifies 97 genetic regions linked to kidney function. These findings aim at better understanding chronic kidney disease in diverse populations.