Search

Ovarian cancer (OC) is the most lethal gynecologic malignancy. Cannabis sativa is being used to treat different medical conditions. We sought to examine the effectiveness of combinations of cannabis compounds against OC. Cytotoxic activity was determined by XTT assay on HTB75 and HTB161 cell lines. Apoptosis and cell cycle were determined by fluorescence-activated cell sorting (FACS). Gene expression was determined by quantitative PCR. The two most active fractions, F5 and F7, from a high Δ9–tetrahydrocannabinol (THC) cannabis strain extract and their standard mix (SM) showed cytotoxic activity against OC cells. The most effective phytocannabinoid combination was THC+cannabichromene (CBC)+cannabigerol (CBG). F5, F7 and SM affected cell cycle, led to cell apoptosis and to a marked reduction in cell migration. Moreover, these fractions act in synergy with niraparib, and were ~50 fold more cytotoxic to OC cells than to normal keratenocytes. Niraparib+F7 treatment was effective on OC patient's cells. F7 and the niraparin+fraction (F5 and F7) treatments reduced Mitogen-Activated Protein Kinase 4 (MAPK4) gene expression; this reduction may act in synergy with the niraparib inhibition of Poly (ADP-ribose) polymerase 1 (PARP1) activity. Combinations of cannabis compounds and niraparib should be examined for efficacy in pre-clinical studies and clinical trials.

Quarantining close contacts of individuals infected with SARS-CoV-2 for 10 to 14 days is a key strategy in reducing transmission. However, quarantine requirements are often unpopular, with low adherence, especially when a large fraction of the population has been vaccinated. Daily contact testing (DCT), in which contacts are required to isolate only if they test positive, is an alternative to quarantine for mitigating the risk of transmission from traced contacts. In this study, we developed an integrated model of COVID-19 transmission dynamics and compared the strategies of quarantine and DCT with regard to reduction in transmission and social/economic costs (days of quarantine/self-isolation). Specifically, we compared 10-day quarantine to 7 days of self-testing using rapid lateral flow antigen tests, starting 3 days after exposure to a case. We modelled both incomplete adherence to quarantine and incomplete adherence to DCT. We found that DCT reduces transmission from contacts with similar effectiveness, at much lower social/economic costs, especially for highly vaccinated populations. The findings were robust across a spectrum of scenarios with varying assumptions on the speed of contact tracing, sensitivity of lateral flow antigen tests, adherence to quarantine and uptake of testing. Daily tests would also allow rapid initiation of a new round of tracing from infected contacts.

Background In May 2020, the UK National Health Service (NHS) Test and Trace programme was launched in England in response to the COVID-19 pandemic. The programme was first rolled out on the Isle of Wight and included version 1 of the NHS contact tracing app. The aim of the study was to make a preliminary assessment of the epidemiological impact of the Test and Trace programme using publicly available data. Methods We used COVID-19 daily case data from Public Health England to infer incidence of new infections and estimate the reproduction number (R) for each of the 150 Upper-Tier Local Authorities (UTLAs) in England and nationally, before and after the launch of the Test and Trace programme on the Isle of Wight. We used Bayesian and maximum-likelihood methods to estimate R and compared the Isle of Wight with other UTLAs using a synthetic control method. Findings We observed significant decreases in incidence and R on the Isle of Wight immediately after the launch of the Test and Trace programme. The Isle of Wight had a marked reduction in R, from 1·3 before the Test and Trace programme to 0·5 after by one of our measures, and went from having the third highest R before the Test and Trace programme, to the twelfth lowest afterwards compared with other UTLAs. Interpretation Our results show that the epidemic on the Isle of Wight was controlled quickly and effectively after the launch of Test and Trace. Our findings highlight the need for further research to determine the causes of the reduction in the spread of the disease, as these could be translated into local and national non-pharmaceutical intervention strategies in the period before a treatment or vaccination for COVID-19 becomes available. Funding Li Ka Shing Foundation and UK Economic and Social Research Council.

Background: The timing of SARS-CoV-2 transmission is a critical factor to understand the epidemic trajectory and the impact of isolation, contact tracing and other non-pharmaceutical interventions on the spread of COVID-19 epidemics. Methods: We examined the distribution of transmission event times with respect to exposure and onset of symptoms. We analysed 119 transmission pairs with known date of onset of symptoms for both index and secondary cases and partial information on their intervals of exposure. We inferred the distribution for generation time and time from onset of symptoms to transmission by maximum likelihood. We modelled different relations between time of infection, onset of symptoms and transmission, inferring the most appropriate one according to the Akaike Information Criterion. Finally, we estimated the fraction of pre-symptomatic and early symptomatic transmissions among all pairs using a Bayesian approach. Findings: For symptomatic individuals, the timing of transmission of SARS-CoV-2 was more directly linked to the onset of clinical symptoms of COVID-19 than to the time since infection. The time of transmission was approximately centered and symmetric around the onset of symptoms, with three quarters of events occurring in the window from 2-3 days before to 2-3 days after. The pre-symptomatic infectious period extended further back in time for individuals with longer incubation periods. Overall, the fraction of transmission from strictly pre-symptomatic infections was high (41%; 95%CI 31-50%), but a comparably large fraction of transmissions occurred on the same day as the onset of symptoms or the next day (35%; 95%CI 26-45%). We caution against overinterpretation of the fraction and timing of late symptomatic transmissions, due to their dependence on behavioural factors and interventions. Interpretation: Infectiousness is causally driven by the onset of symptoms. Public health authorities should reassess their policies on the contact tracing window in the light of individual variability in presymptomatic infectious period. Information about when a case was infected should be collected where possible, in order to assess how far into the past their contacts should be traced. The large fraction of transmission from strictly pre-symptomatic infections limits the efficacy of symptom-based interventions, while the large fraction of early symptomatic transmissions underlines the critical importance of individuals distancing themselves from others as soon as they notice any symptoms, even if mild. Rapid or at-home testing and contextual risk information could greatly facilitate efficient early isolation. Funding Statement: The study was funded by an award from the Li Ka Shing Foundation to CF. Declaration of Interests: None of the authors have competing financial or non-financial interests.

Background Multidrug-resistant tuberculosis poses a major threat to the success of tuberculosis control programs worldwide. Understanding how drug-resistant tuberculosis evolves can inform the development of new therapeutic and preventive strategies. Methods Here, we use novel genome-wide analysis techniques to identify polymorphisms that are associated with drug resistance, adaptive evolution and the structure of the phylogenetic tree. A total of 471 samples from different patients collected between 2009 and 2013 in the Lima suburbs of Callao and Lima South were sequenced on the Illumina MiSeq platform with 150bp paired-end reads. After alignment to the reference H37Rv genome, variants were called using standardized methodology. Genome-wide analysis was undertaken using custom written scripts implemented in R software. Results High quality homoplastic single nucleotide polymorphisms were observed in genes known to confer drug resistance as well as genes in the Mycobacterium tuberculosis ESX secreted protein pathway, pks12, and close to toxin/anti-toxin pairs. Correlation of homoplastic variant sites identified that many were significantly correlated, suggestive of epistasis. Variation in genes coding for ESX secreted proteins also significantly disrupted phylogenetic structure. Mutations in ESX genes in key antigenic epitope positions were also found to disrupt tree topology. Conclusions Variation in these genes have a biologically plausible effect on immunogenicity and virulence. This makes functional characterization warranted to determine the effects of these polymorphisms on bacterial fitness and transmission.