5 months into the monkeypox epidemic, there are no proven therapies and no comparative safety and efficacy data in the treatment of affected individuals. The question remains whether we, as a ...scientific and medical community, will apply the lessons learned from the past decade of outbreaks that well conducted randomised controlled trials can be ethically, safely, and efficiently performed to guide clinical decision making so that the right drug is used for the right patient at the right time. Furthermore, the robust level of evidence from randomised controlled trials is highly relevant to advocating for equitable access to new treatments in low-income and middle-income countries. As with COVID-19, we need to pair optimal supportive care with rigorously designed double-blind randomised controlled trials to elucidate safe and effective therapies for monkeypox. The need remains for the funding and development of predesigned, adaptive trial protocols for diseases with epidemic or pandemic potential that can be timely pulled off the shelf and launched early in an outbreak, leveraging ready clinical trial networks and infrastructure for rapid discovery and implementation of new treatments.
Abstract
Lipid- and lipoprotein-modifying therapies have expanded substantially in the last 25 years, resulting in reduction in the incidence of major adverse cardiovascular events. However, no ...specific lipoprotein(a) Lp(a)-targeting therapy has yet been shown to reduce cardiovascular disease risk. Many epidemiological and genetic studies have demonstrated that Lp(a) is an important genetically determined causal risk factor for coronary heart disease, aortic valve disease, stroke, heart failure, and peripheral vascular disease. Accordingly, the need for specific Lp(a)-lowering therapy has become a major public health priority. Approximately 20% of the global population (1.4 billion people) have elevated levels of Lp(a) associated with higher cardiovascular risk, though the threshold for determining ‘high risk’ is debated. Traditional lifestyle approaches to cardiovascular risk reduction are ineffective at lowering Lp(a). To address a lifelong risk factor unmodifiable by non-pharmacological means, Lp(a)-lowering therapy needs to be safe, highly effective, and tolerable for a patient population who will likely require several decades of treatment. N-acetylgalactosamine-conjugated gene silencing therapeutics, such as small interfering RNA (siRNA) and antisense oligonucleotide targeting LPA, are ideally suited for this application, offering a highly tissue- and target transcript-specific approach with the potential for safe and durable Lp(a) lowering with as few as three or four doses per year. In this review, we evaluate the causal role of Lp(a) across the cardiovascular disease spectrum, examine the role of established lipid-modifying therapies in lowering Lp(a), and focus on the anticipated role for siRNA therapeutics in treating and preventing Lp(a)-related disease.
Graphical Abstract
The LPA gene encodes apolipoprotein (a), a key component of Lp(a), a potent risk factor for cardiovascular disease with no specific pharmacotherapy. Here we describe the pharmacological data for ...SLN360, a GalNAc-conjugated siRNA targeting LPA, designed to address this unmet medical need.
SLN360 was tested in vitro for LPA knockdown in primary hepatocytes. Healthy cynomolgus monkeys received single or multiple subcutaneous doses of the SLN360 sequence ranging from 0.1 to 9.0 mg/kg to determine the pharmacokinetic and pharmacodynamic effects. Liver mRNA and serum biomarker analyses were performed.
In vitro, the SLN360 sequence potently reduces LPA mRNA in primary cynomolgus and human hepatocytes, while no effect was observed on the expression of APOB or PLG. In vivo, SLN360 exposure peaks 2 h after subcutaneous injection with near full elimination by 24 h. Specific LPA mRNA reduction (up to 91% 2 weeks after dosing) was observed with only the 3 mg/kg group showing appreciable return to baseline (40%). No consistent dose- or time-dependent effect on the expression of APOB, PLG or a panel of sensitive markers of liver lipid accumulation was observed. Potent (up to 95%) and long lasting (≥9 weeks) serum Lp(a) reduction was observed, peaking in all active groups at day 21. The minimally effective dose was determined to be 0.3 mg/kg with an ED50 of 0.6 mg/kg.
SLN360 induces a sustained reduction in serum Lp(a) levels in cynomolgus monkeys following subcutaneous dosing. SLN360 has potential to address the unmet need of Lp(a) reduction in cardiovascular diseases.
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•Elevated Lipoprotein (a) Lp(a) is a potent risk factor for cardiovascular disease.•Lp(a) levels are genetically determined; lifestyle changes have no effect on levels.•SLN360 is a GalNAc-conjugated siRNA that specifically targets LPA mRNA in the liver.•SLN360 induces a persistent and deep reduction in serum Lp(a) in non-human primates.•SLN360 can address the unmet need of Lp(a) reduction in cardiovascular diseases.
Genomics and the origin of species Seehausen, Ole; Butlin, Roger K; Keller, Irene ...
Nature reviews. Genetics,
03/2014, Volume:
15, Issue:
3
Journal Article
Peer reviewed
Open access
Speciation is a fundamental evolutionary process, the knowledge of which is crucial for understanding the origins of biodiversity. Genomic approaches are an increasingly important aspect of this ...research field. We review current understanding of genome-wide effects of accumulating reproductive isolation and of genomic properties that influence the process of speciation. Building on this work, we identify emergent trends and gaps in our understanding, propose new approaches to more fully integrate genomics into speciation research, translate speciation theory into hypotheses that are testable using genomic tools and provide an integrative definition of the field of speciation genomics.
The rapid spread of the highly contagious Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) along with its high number of mutations in the spike gene has raised alarms ...about the effectiveness of current medical countermeasures. To address this concern, we measured the neutralization of the Omicron BA.1 variant pseudovirus by postvaccination serum samples after two and three immunizations with the Pfizer/BioNTech162b2 SARS-CoV-2 mRNA (Pfizer/BNT162b2) vaccine, convalescent serum samples from unvaccinated individuals infected by different variants, and clinical-stage therapeutic antibodies. We found that titers against the Omicron variant were low or undetectable after two immunizations and in many convalescent serum samples, regardless of the infecting variant. A booster vaccination increased titers more than 30-fold against Omicron to values comparable to those seen against the D614G variant after two immunizations. Neither age nor sex was associated with the differences in postvaccination antibody responses. We also evaluated 18 clinical-stage therapeutic antibody products and an antibody mimetic protein product obtained directly from the manufacturers. Five monoclonal antibodies, the antibody mimetic protein, three antibody cocktails, and two polyclonal antibody preparations retained measurable neutralization activity against Omicron with a varying degree of potency. Of these, only three retained potencies comparable to the D614G variant. Two therapeutic antibody cocktails in the tested panel that are authorized for emergency use in the United States did not neutralize Omicron. These findings underscore the potential benefit of mRNA vaccine boosters for protection against Omicron and the need for rapid development of antibody therapeutics that maintain potency against emerging variants.
Arboviral infections, including dengue (DNV), chikungunya (CHIKV), and Zika (ZIKV), impact both travelers and native populations of endemic regions. We sought to assess the disease burden of ...arboviral infections in the Military Health System, the validity of arboviral diagnostic codes, and the role of pretravel counseling on insect avoidance precautions. We searched for diagnostic codes consistent with arboviral infection and grouped them into DNV, CHIKV, ZIKV, Japanese encephalitis virus (JEV), and Other. Demographic data were evaluated. A subset of charts in each category were reviewed for diagnostic validity and travel characteristics. In all, 10,547 unique subjects carried 17,135 arboviral diagnostic codes, including 1,606 subjects (15.2%) coded for DNV, 230 (2.2%) for ZIKV, 65 (0.6%) for CHIKV, and 4,317 (40.9%) for JEV. A chart review was performed on 807 outpatient charts, yielding outpatient diagnostic code positive predictive values of 60.5% (DNV), 15.3% (ZIKV), and 64.5% (CHIKV); there were no valid cases of JEV. Dengue represented the greatest burden of arboviral infections with 2.2 cases per 100,000 military healthcare enrollees over the 2012-2019 fiscal years. More than 80% of subjects with arboviral infection did not have documented pretravel counseling. Arboviral infections represent a significant disease burden in young travelers to endemic regions. After adjustment for diagnostic validity, DNV represented the greatest burden. Diagnostic codes for ZIKV and JEV overestimate the burden of these diseases. Low rates of pretravel visits represent an opportunity for increased emphasis on insect exposure precautions.
chronic infection is frequently subclinical and thus under-recognized, although its increasing prevalence in nonendemic regions has implications for immunocompromised hosts. We present a 75-year-old ...male with stage II multiple myeloma who presented with relapse of
infection after initial treatment, negative surveillance testing, and subsequent resumption of chemotherapy for his multiple myeloma. The optimal regimen for secondary prophylaxis against recurrent infections is unknown. Secondary prophylaxis should be considered for patients who recur and/or remain at high risk of recurrence because of ongoing immunosuppression. We implemented a prophylactic regimen of ivermectin 200 mcg/kg once monthly. In addition, improved laboratory assays for strongyloidiasis are needed to aid with diagnosis, monitoring of treatment response, and early detection of relapse.
Accurate COVID-19 prognosis is a critical aspect of acute and long-term clinical management. We identified discrete clusters of early stage-symptoms which may delineate groups with distinct disease ...severity phenotypes, including risk of developing long-term symptoms and associated inflammatory profiles.
1,273 SARS-CoV-2 positive U.S. Military Health System beneficiaries with quantitative symptom scores (FLU-PRO Plus) were included in this analysis. We employed machine-learning approaches to identify symptom clusters and compared risk of hospitalization, long-term symptoms, as well as peak CRP and IL-6 concentrations.
We identified three distinct clusters of participants based on their FLU-PRO Plus symptoms: cluster 1 ("Nasal cluster") is highly correlated with reporting runny/stuffy nose and sneezing, cluster 2 ("Sensory cluster") is highly correlated with loss of smell or taste, and cluster 3 ("Respiratory/Systemic cluster") is highly correlated with the respiratory (cough, trouble breathing, among others) and systemic (body aches, chills, among others) domain symptoms. Participants in the Respiratory/Systemic cluster were twice as likely as those in the Nasal cluster to have been hospitalized, and 1.5 times as likely to report that they had not returned-to-activities, which remained significant after controlling for confounding covariates (P < 0.01). Respiratory/Systemic and Sensory clusters were more likely to have symptoms at six-months post-symptom-onset (P = 0.03). We observed higher peak CRP and IL-6 in the Respiratory/Systemic cluster (P < 0.01).
We identified early symptom profiles potentially associated with hospitalization, return-to-activities, long-term symptoms, and inflammatory profiles. These findings may assist in patient prognosis, including prediction of long COVID risk.
The rapid emergence of SARS-CoV-2 variants challenges vaccination strategies. Here, we collected 201 serum samples from persons with a single infection or multiple vaccine exposures, or both. We ...measured their neutralization titers against 15 natural variants and 7 variants with engineered spike mutations and analyzed antigenic diversity. Antigenic maps of primary infection sera showed that Omicron sublineages BA.2, BA.4/BA.5, and BA.2.12.1 are distinct from BA.1 and more similar to Beta/Gamma/Mu variants. Three mRNA COVID-19 vaccinations increased neutralization of BA.1 more than BA.4/BA.5 or BA.2.12.1. BA.1 post-vaccination infection elicited higher neutralization titers to all variants than three vaccinations alone, although with less neutralization to BA.2.12.1 and BA.4/BA.5. Those with BA.1 infection after two or three vaccinations had similar neutralization titer magnitude and antigenic recognition. Accounting for antigenic differences among variants when interpreting neutralization titers can aid the understanding of complex patterns in humoral immunity that informs the selection of future COVID-19 vaccine strains.
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•Antigenic cartography of convalescent sera shows BA.1 as the most distinct variant•SARS-CoV-2 convalescent or vaccinee sera distinguish BA.1 and BA.4/BA.5 variants•Third vaccine boosts BA.1 and BA.2 neutralization more than BA.2.12.1 and BA.4/BA.5•BA.1 infection after two or three vaccinations broadens neutralization similarly
Wang et al. show that SARS-CoV-2 Omicron BA.1 or BA.1.1 infection after a second or third mRNA COVID-19 vaccination broadens neutralizing antibody responses to all variants, including Omicron, more than three vaccinations alone. BA.2.12.1 and BA.4/BA.5 evade neutralization more than BA.1 and BA.2 after three vaccinations or Omicron infection post-vaccination.
Abstract Background Post-COVID conditions (PCC) are difficult to characterize, diagnose, predict, and treat due to overlapping symptoms and poorly understood pathology. Identifying inflammatory ...profiles may improve clinical prognostication and trial endpoints. Methods This analysis included 1988 SARS-CoV-2 positive U.S. Military Health System beneficiaries who had quantitative post–COVID symptom scores. Among participants who reported moderate-to-severe symptoms on surveys collected 6 months post-SARS-CoV-2 infection, principal component analysis followed by k-means clustering identified distinct clusters of symptoms. Results Three symptom-based clusters were identified: a sensory cluster (loss of smell and/or taste), a fatigue/difficulty thinking cluster, and a difficulty breathing/exercise intolerance cluster. Individuals within the sensory cluster were all outpatients during their initial COVID-19 presentation. The difficulty breathing cluster had a higher likelihood of obesity and COVID-19 hospitalization than those with no/mild symptoms at 6 months post-infection. Multinomial regression linked early post-infection D-dimer and IL-1RA elevation to fatigue/difficulty thinking and elevated ICAM-1 concentrations to sensory symptoms. Conclusions We identified three distinct symptom-based PCC phenotypes with specific clinical risk factors and early post-infection inflammatory predictors. With further validation and characterization, this framework may allow more precise classification of PCC cases and potentially improve the diagnosis, prognostication, and treatment of PCC.
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