Engagement With Daily Testing Instead of Self-Isolating in Contacts of Confirmed Cases of SARS-CoV-2:A Qualitative Analysis

Introduction: In December 2020 and January 2021 Public Health England (PHE) with NHS Test and Trace conducted a study to explore the feasibility and acceptability of daily testing as an alternative to self-isolation following close contact with a confirmed COVID-19 case. This qualitative paper aims to identify factors influencing uptake among those offered daily testing, and the subsequent impact on behaviour. Methods: We conducted in-depth interviews with 52 participants who had taken part in the feasibility study. Participants were asked about their experiences of daily testing or self-isolating, their reasons for choosing to test or isolate, and their behaviour during the study period. Data were analysed using inductive thematic analysis. Results: Results are presented under two main headings: (1) factors influencing acceptance of testing and (2) impact of test results. Participants appeared highly motivated to engage in behaviours that would protect others from the virus. Factors influencing the decision to accept testing included (1) needing to avoid self-isolation, (2) concerns about test sensitivity, and (3) perceived benefits of detecting infection. Participants who were taking tests reported: (1) positive consequences following confirmation of COVID status, (2) engaging in essential activities, (3) uncertainty, and (4) self-isolating whilst testing. Conclusions: This study has identified a range of factors that appear to influence the decision to engage in daily testing or to self-isolate following close contact with a positive case, many of which could be addressed by clear communications. Covid-19 infection rates and government restrictions influenced experiences, and so further research is needed to explore perceptions of daily testing and behaviour following close contact with a positive case among a wider range of individuals, in the context of lower rates of COVID-19, few government restrictions on general population behaviour and more widespread testing

A Mild and Efficient Synthesis of Oxindoles: Progress Towards the Synthesis of Welwitindolinone A Isonitrile

The complete carbon skeleton of welwitindolinone A isonitrile has been prepared by using a [2+2] cycloaddition to establish the bicyclo[4.2.0]octane core and a SmI2-mediated intramolecular reductive cyclization between an enone and an aryl isocyanate to stereoselectively install the spiro-oxindole (see scheme; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene)

Total Synthesis of (±)-Welwitindolinone A Isonitrile

A highly stereoselective total synthesis of the alkaloid natural product welwitindolinone A isonitrile has been completed. The synthesis utilizes a chloronium ion mediated semi-pinacol rearrangement to simultaneously install the C10 quaternary center and neopentyl chlorine and a novel anionic cyclization to construct the spiro-oxindole with complete stereocontrol

Daily use of lateral flow devices by contacts of confirmed COVID-19 cases to enable exemption from isolation compared with standard self-isolation to reduce onward transmission of SARS-CoV-2 in England:a randomised, controlled, non-inferiority trial

Background: In the UK, during the study period all COVID-19 contacts were required to self-isolate for 10 days, which had adverse impacts. Avoiding the need to self-isolate for those who remain uninfected would be beneficial to society. We investigated whether using daily lateral flow devices (LFDs) to test for COVID-19 with removal of self-isolation for 24 hours if negative was a safe alternative to self-isolation by determining tertiary attack rates (proportion being infected) in study groups.Methods: We conducted a non-inferiority randomised controlled trial (Research Registry ID:6809) in adult contacts identified during COVID-19 contact tracing. Consented participants were randomised to self-isolation (SI; single PCR, 10 days isolation) or daily contact-testing (DCT; 7 LFDs, 2 PCRs, no isolation if negative on LFD);participants from a household were assigned to the same arm. Participants were prospectively followed-up with the impact of each intervention on onward transmission determined from routinely collected contact tracing data for COVID-19 participants, and tertiary cases arising from their contacts. Attack rates were derived from cluster-robust standard error Bernoulli regression models. Questionnaires were sent at recruitment and at the end of testing/self-isolation to assess behaviours.Findings: 49,623 individuals consented to participate with final arm allocations of 26,123 DCT (52.6%) and 23,500 SI participants (47.4%). Overall. 4,561 participants tested positive by PCR (secondary cases); 2,359 (10.0%) in the SI arm and 2,202 (8.4%) in the DCT arm. Tertiary attack rates (among secondary contacts) were 7.5% in SI arm and 6.4% in DCT arm (difference of -1.1 % (95% Confidence Interval -2.2% to -0.03%)), significantly lower than the non-inferiority margin of 1.9%.124,010 valid LFD results were reported from 20,795 (79.6%) DCT participants with 1,132 (5.4%) reporting a positive result. Interpretation: DCT with 24-hour exemption from self-isolation for essential activities appears to be non-inferior to self-isolation.Interpretation: DCT with 24-hour exemption from self-isolation for essential activities appears to be non-inferior to self-isolation.<br/

Evolution of a Synthetic Strategy: Total Synthesis of (±)-Welwitindolinone A Isonitrile

An efficient and highly stereoselective total synthesis of the natural product (±)-welwitindolinone A isonitrile (1) is described. The bicyclo[4.2.0]octane core of 1 was established by a regio- and diastereoselective [2+2] ketene cycloaddition. The C12 quaternary center and vicinal stereogenic chlorine were installed in a single operation with excellent stereocontrol via a chloronium ion mediated semipinacol rearrangement. Described strategies for construction of the spiro-oxinole include a SmI_2−LiCl mediated reductive cyclization and a novel anionic cyclization that simultaneously constructs the spiro-oxindole and vinyl isonitrile moieties

Imaging of Light-Enhanced Extracellular Vesicle-Mediated Delivery of Oxaliplatin to Colorectal Cancer Cells via Laser Ablation, Inductively Coupled Plasma Mass Spectrometry

Extracellular vesicles (EVs) are lipid bilayer structures released by all cells that mediate cell-to-cell communication via the transfer of bioactive cargo. Because of the natural origin of EVs, their efficient uptake by recipient cells, capacity to stabilize and transport biomolecules and their potential for cell/tissue targeting and preferential uptake by cancer cells, they have enormous potential for bioengineering into improved and targeted drug delivery systems. In this work, we investigated the use of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) as a tool to measure the loading of platinum-based chemotherapeutic agents. The EV loading of oxaliplatin via co-incubation was demonstrated, and LA-ICP-MS imaging showed greater efficiency of delivery to colorectal cancer cells compared to free oxaliplatin, leading to enhanced cytotoxic effect. Further, the impact of EV co-loading with a porphyrin (C5SHU, known as ‘C5’) photosensitizer on oxaliplatin delivery was assessed. Fluorescence analysis using nano-flow cytometry showed dose-dependent EV loading as well as a trend towards the loading of larger particles. Exposure of OXA-C5-EV-treated colorectal cancer cells to light indicated that delivery was enhanced by both light exposure and porphyrins, with a synergistic effect on cell viability observed between oxaliplatin, EVs and light exposure after the delivery of the co-loaded EVs. In summary, this work demonstrates the utility of LA-ICP-MS and mass spectrometry imaging in assessing the loading efficiency and cellular delivery of platinum-based therapeutics, which would also be suitable for agents containing other elements, confirms that EVs are more efficient at delivery compared to free drugs, and describes the use of light exposure in optimizing delivery and therapeutic effects of EV-mediated drug delivery both in combination and independently of porphyrin-based photosensitizers

Understanding the transmission dynamics of Leishmania donovani to provide robust evidence for interventions to eliminate visceral leishmaniasis in Bihar, India.

Visceral Leishmaniasis (VL) is a neglected vector-borne disease. In India, it is transmitted to humans by Leishmania donovani-infected Phlebotomus argentipes sand flies. In 2005, VL was targeted for elimination by the governments of India, Nepal and Bangladesh by 2015. The elimination strategy consists of rapid case detection, treatment of VL cases and vector control using indoor residual spraying (IRS). However, to achieve sustained elimination of VL, an appropriate post elimination surveillance programme should be designed, and crucial knowledge gaps in vector bionomics, human infection and transmission need to be addressed. This review examines the outstanding knowledge gaps, specifically in the context of Bihar State, India.The knowledge gaps in vector bionomics that will be of immediate benefit to current control operations include better estimates of human biting rates and natural infection rates of P. argentipes, with L. donovani, and how these vary spatially, temporally and in response to IRS. The relative importance of indoor and outdoor transmission, and how P. argentipes disperse, are also unknown. With respect to human transmission it is important to use a range of diagnostic tools to distinguish individuals in endemic communities into those who: 1) are to going to progress to clinical VL, 2) are immune/refractory to infection and 3) have had past exposure to sand flies.It is crucial to keep in mind that close to elimination, and post-elimination, VL cases will become infrequent, so it is vital to define what the surveillance programme should target and how it should be designed to prevent resurgence. Therefore, a better understanding of the transmission dynamics of VL, in particular of how rates of infection in humans and sand flies vary as functions of each other, is required to guide VL elimination efforts and ensure sustained elimination in the Indian subcontinent. By collecting contemporary entomological and human data in the same geographical locations, more precise epidemiological models can be produced. The suite of data collected can also be used to inform the national programme if supplementary vector control tools, in addition to IRS, are required to address the issues of people sleeping outside

Outcome and biomarker analysis from a multi-centre phase 2 study of ipilimumab in combination with carboplatin and etoposide (ICE) as first line therapy for extensive stage small cell lung cancer.

BACKGROUND: To evaluate safety and efficacy of ipilimumab combined with standard first-line chemotherapy for patients with extensive stage SCLC. METHODS: Chemotherapy-naïve extensive stage SCLC patients were treated with carboplatin and etoposide up to six cycles. Ipilimumab 10 mg/kg was given on day 1 of cycles 3-6 and every 12 weeks. Response was assessed by RECIST v1.0 and immune related response criteria (irRC). The primary endpoint was 1-year progression-free survival (PFS) according to RECIST. Secondary endpoints included PFS by irRC (irPFS) and overall survival (OS). Autoantibody serum levels were evaluated and correlated with clinical outcomes. RESULTS: 42 patients were enrolled between September 2011-April 2014, 39 evaluable for safety and 38 for efficacy. 6/38 patients (15.8% [95% CI: 7.4%-30.4%]) were alive and progression-free at 1-year by RECIST. Median PFS was 6.9 months (95%CI: 5.5-7.9). Median irPFS was 7.3 months (95% CI: 5.5-8.8). Median OS was 17.0 months (95% CI: 7.9-24.3). In patients evaluable for response, 21/29 patients (72.4%) achieved an objective response by RECIST and 28/33 (84.8%) by irRC. All patients experienced at least one adverse event; 35/39 (89.7%) patients developed at least one toxicity ≥ Grade 3; in 27 (69.2%) this was related to ipilimumab. Five deaths were reported to be related to ipilimumab. The positivity of an autoimmune profile at baseline was associated with improved outcomes and severe neurological toxicity. CONCLUSION: Ipilimumab in combination with carboplatin and etoposide might benefit a subgroup of patients with advanced SCLC. Autoantibody analysis correlates with treatment benefit and toxicity and warrants further investigation