Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial.

BACKGROUND: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. METHODS: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. INTERPRETATION: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. FUNDING: UK National Institute for Health and Care Research.

Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial.

BACKGROUND: A previous efficacy trial found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown. We aimed to establish whether inhaled budesonide reduces time to recovery and COVID-19-related hospital admissions or deaths among people at high risk of complications in the community. METHODS: PRINCIPLE is a multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial done remotely from a central trial site and at primary care centres in the UK. Eligible participants were aged 65 years or older or 50 years or older with comorbidities, and unwell for up to 14 days with suspected COVID-19 but not admitted to hospital. Participants were randomly assigned to usual care, usual care plus inhaled budesonide (800 µg twice daily for 14 days), or usual care plus other interventions, and followed up for 28 days. Participants were aware of group assignment. The coprimary endpoints are time to first self-reported recovery and hospital admission or death related to COVID-19, within 28 days, analysed using Bayesian models. The primary analysis population included all eligible SARS-CoV-2-positive participants randomly assigned to budesonide, usual care, and other interventions, from the start of the platform trial until the budesonide group was closed. This trial is registered at the ISRCTN registry (ISRCTN86534580) and is ongoing. FINDINGS: The trial began enrolment on April 2, 2020, with randomisation to budesonide from Nov 27, 2020, until March 31, 2021, when the prespecified time to recovery superiority criterion was met. 4700 participants were randomly assigned to budesonide (n=1073), usual care alone (n=1988), or other treatments (n=1639). The primary analysis model includes 2530 SARS-CoV-2-positive participants, with 787 in the budesonide group, 1069 in the usual care group, and 974 receiving other treatments. There was a benefit in time to first self-reported recovery of an estimated 2·94 days (95% Bayesian credible interval [BCI] 1·19 to 5·12) in the budesonide group versus the usual care group (11·8 days [95% BCI 10·0 to 14·1] vs 14·7 days [12·3 to 18·0]; hazard ratio 1·21 [95% BCI 1·08 to 1·36]), with a probability of superiority greater than 0·999, meeting the prespecified superiority threshold of 0·99. For the hospital admission or death outcome, the estimated rate was 6·8% (95% BCI 4·1 to 10·2) in the budesonide group versus 8·8% (5·5 to 12·7) in the usual care group (estimated absolute difference 2·0% [95% BCI -0·2 to 4·5]; odds ratio 0·75 [95% BCI 0·55 to 1·03]), with a probability of superiority 0·963, below the prespecified superiority threshold of 0·975. Two participants in the budesonide group and four in the usual care group had serious adverse events (hospital admissions unrelated to COVID-19). INTERPRETATION: Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications. FUNDING: National Institute of Health Research and United Kingdom Research Innovation.

High Na+ Mobility in rGO Wrapped High Aspect Ratio 1D SbSe Nano Structure Renders Better Electrochemical Na+ Battery Performance.

We chose to understand the cyclic instability and rate instability issues in the promising class of Na+ conversion and alloying anodes with Sb2 Se3 as a typical example. We employ a synthetic strategy that ensures efficient rGO (reduced graphene oxide) wrapping over Sb2 Se3 material. By utilization of the minimum weight of additive (5 wt.% of rGO), we achieved a commendable performance with a reversible capacity of 550 mAh g-1 at a specific current of 100 mA g-1 and an impressive rate performance with 100 % capacity retention after high current cycling involving a 2 Ag-1 intermediate current step. The electrochemical galvanostatic intermittent titration technique (GITT) has been employed for the first time to draw a rationale between the enhanced performance and the increased mobility in the rGO wrapped composite (Sb2 Se3 -rGO) compared to bare Sb2 Se3 . GITT analysis reveals higher Na+ diffusion coefficients (approx. 30 fold higher) in the case of Sb2 Se3 -rGO as compared to bare Sb2 Se3 throughout the operating voltage window. For Sb2 Se3 -rGO the diffusion coefficients in the range of 8.0×10-15  cm2 s-1 to 2.2×10-12  cm2 s-1 were observed, while in case of bare Sb2 Se3 the diffusion coefficients in the range of 1.6×10-15  cm2 s-1 to 9.4×10-15  cm2 s-1 were observed.

Can an ammonium-based room temperature ionic liquid counteract the urea-induced denaturation of a small peptide?

The folding/unfolding equilibrium of proteins in aqueous medium can be altered by adding small organic molecules generally termed as co-solvents. Denaturants such as urea are instrumental in the unfolding of proteins while protecting osmolytes favour the folded ensemble. Recently, room temperature ionic liquids (ILs) have been shown to counteract the deleterious effect of urea on proteins. In this paper, using atomistic molecular dynamics we show that a ternary mixture containing a particular ammonium-based IL, triethylammonium acetate (TEAA), and urea (in 1 : 5 molar ratio) helps a small 15-residue S-peptide analogue regain most of its native structure, whereas a binary aqueous mixture containing a large amount of urea alone completely distorts it. Our simulations show that the denaturant urea directly interacts with the peptide backbone in the binary mixture while for the ternary mixture both urea as well as the IL are preferentially excluded from the peptide surface.

Endovascular Embolization in a Rare Case of Left Basal Ganglia Large Arteriovenous Malformation with Hydrocephalus: A Case Report.

Brain arteriovenous malformation (AVM) is a rare congenital disorder affecting young adults with an incidence of 0.94 per 100,000 population. Intracranial digital subtraction angiography has to be done in all patients and grading of AVM is done as per Spetzler-Martin grading. We report a rare case of left basal ganglia large AVM treated by endovascular embolization. Our experience with endovascular embolization using Onyx is successful in the treatment of large brain AVM. Endovascular embolization with Onyx is safe and feasible in deeply located large AVMs of the brain. Our patient has postoperatively recovered completely without any neurological deficit.

Missed Opportunities in Type 2 Diabetes Mellitus: A Narrative Review.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a significant health problem around the world. OBJECTIVE: This review aims to define missed opportunities and how they apply to patients with T2DM. METHOD: This narrative review describes the natural history of T2DM and also describes where missed opportunities may arise. RESULTS: Missed opportunities may relate to prevention, early detection, diagnosis, and treatment of diabetes. The cornerstone of T2DM prevention is the control of modifiable risk factors and lifestyle changes to potentially prevent diabetes. Early detection of T2DM is important as it is a chronic condition that can progress rapidly if untreated. Missed opportunities related to the diagnosis of T2DM draw attention to the heterogeneous presentation of diabetes. The condition can be incidentally identified in asymptomatic patients, so all healthcare professionals should be aware of the disease. Furthermore, it is not unexpected that patients with atypical symptoms may have a delay in diagnosis. The treatment-related missed opportunities in T2DM are broad and include self-care, education, remission of T2DM, risk factor management, prevention of complications, medication therapy and compliance, as well as individualized care. Considering patient pathways is a useful approach to evaluate missed opportunities in patient care. CONCLUSION: Missed opportunities are a concept that is not often considered in diabetes care, which calls upon reflection of real-world activities and consideration of whether patient outcomes could have been improved with changes in decision-making. Future studies that aim to improve patient care should consider this concept.

Low-Carbohydrate and Ketogenic Dietary Patterns for Type 2 Diabetes Management.

Background: Type 2 diabetes mellitus (T2DM) has been traditionally considered a chronic, progressive disease. Since 2017, guidelines from the US Department of Veterans Affairs and US Department of Defense have included low-carbohydrate (LC) dietary patterns in managing T2DM. Recently, carbohydrate reduction, including ketogenic diets, has gained renewed interest in the management and remission of T2DM. Observations: This narrative review examines the evidence behind carbohydrate reduction in T2DM and a practical guide for clinicians starting patients on therapeutic LC diets. We present an illustrative case and provide practical approaches to prescribing a very LC ketogenic (< 50 g), LC (50-100 g), or a moderate LC (101-150 g) dietary plan and discuss adverse effects and management of LC diets. We provide a medication management and deprescription approach and discuss strategies to consider in conjunction with LC diets. As patients adopt LC diets, glycemia improves, and medications are deprescribed, hemoglobin A1c levels and fasting glucose may drop below the diagnostic threshold for T2DM. Remission of T2DM may occur with LC diets (hemoglobin A1c < 6.5% for ≥ 3 months without T2DM medications). Finally, we describe barriers and limitations to applying therapeutic carbohydrate reduction in a federal health care system. Conclusions: The effective use of LC diets with close and intensive lifestyle counseling and a safe approach to medication management and deprescribing can improve glycemic control, reduce the overall need for insulin and medication and provide sustained weight loss. The efficacy and continuation of therapeutic carbohydrate reduction for patients with T2DM appears promising. Further research on LC diets, emerging strategies, and long-term effects on cardiometabolic risk factors, morbidity, and mortality will continue to inform practice.

Favipiravir for COVID-19 in adults in the community in PRINCIPLE, an open-label, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: Evidence for the effect of favipiravir treatment of acute COVID-19 on recovery, hospital admissions and longer-term outcomes in community settings is limited. METHODS: In this multicentre. open-label, multi-arm, adaptive platform randomised controlled trial participants aged ≥18 years in the community with a positive test for SARS-CoV-2 and symptoms lasting ≤14 days were randomised to: usual care; usual care plus favipiravir tablets (loading dose of 3600 mg in divided doses on day one, then 800 mg twice a day for four days); or, usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Recovery at six months was the primary longer-term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis model included 8811 SARS-CoV-2 positive mostly COVID vaccinated participants, randomised to favipiravir (n = 1829), usual care (n = 3256), and other treatments (n = 3726). Time to self-reported recovery was shorter in the favipiravir group than usual care (estimated hazard ratio 1·23 [95% credible interval 1·14 to 1·33]), a reduction of 2·98 days [1·99 to 3·94] from 16 days in median time to self-reported recovery for favipiravir versus usual care alone. COVID-19 related hospitalisations/deaths were similar (estimated odds ratio 0·99 [0·61 to 1·61]; estimated difference 0% [-0·9% to 0·6%]). 14 serious adverse events occurred in the favipiravir group and 4 in usual care. By six months, the proportion feeling fully recovered was 74·9% for favipiravir versus 71·3% for usual care (RR = 1·05, [1·02 to 1·08]). INTERPRETATION: In this open-label trial in a largely vaccinated population with COVID-19 in the community, favipiravir did not reduce hospital admissions, but shortened time to recovery and had a marginal positive impact on long term outcomes.

Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes.

BACKGROUND: The evidence for whether ivermectin impacts recovery, hospital admissions, and longer-term outcomes in COVID-19 is contested. The WHO recommends its use only in the context of clinical trials. METHODS: In this multicentre, open-label, multi-arm, adaptive platform randomised controlled trial, we included participants aged ≥18 years in the community, with a positive SARS-CoV-2 test, and symptoms lasting ≤14 days. Participants were randomised to usual care, usual care plus ivermectin tablets (target 300-400 µg/kg per dose, once daily for 3 days), or usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery, and COVID-19 related hospitalisation/death within 28 days, analysed using Bayesian models. Recovery at 6 months was the primary, longer term outcome. TRIAL REGISTRATION: ISRCTN86534580. FINDINGS: The primary analysis included 8811 SARS-CoV-2 positive participants (median symptom duration 5 days), randomised to ivermectin (n = 2157), usual care (n = 3256), and other treatments (n = 3398) from June 23, 2021 to July 1, 2022. Time to self-reported recovery was shorter in the ivermectin group compared with usual care (hazard ratio 1·15 [95% Bayesian credible interval, 1·07 to 1·23], median decrease 2.06 days [1·00 to 3·06]), probability of meaningful effect (pre-specified hazard ratio ≥1.2) 0·192). COVID-19-related hospitalisations/deaths (odds ratio 1·02 [0·63 to 1·62]; estimated percentage difference 0% [-1% to 0·6%]), serious adverse events (three and five respectively), and the proportion feeling fully recovered were similar in both groups at 6 months (74·3% and 71·2% respectively (RR = 1·05, [1·02 to 1·08]) and also at 3 and 12 months. INTERPRETATION: Ivermectin for COVID-19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. FUNDING: UKRI/National Institute of Health Research (MC_PC_19079).

Evaluation of Sealing Ability of MTA Flow, Biodentine and Pro-Root MTA to Seal the Furcal Perforation with and without Internal Matrix- An In vitro Study.

Introduction: Endodontic mistakes, also known as procedural accidents, are those bad events that occur during treatment, some of which are attributable to a lack of attention to detail and others of which are completely unforeseeable. The second most frequent reason for root canal failure is perforation. Aims and Objective: The current in vitro study's objective was to assess the furcal perforation's potential to be sealed with and without internal matrix by MTA flow, Biodentine, and pro-root MTA. Materials and Methods: 60 samples were allocated into six groups at random (10 each). In intact permanent mandibular first and second teeth, furcal perforation sites were made and sealed with various materials. Following perforation sealing, the specimens' capacity for sealing was evaluated using the dye penetration method. Result: The current study's findings indicated that Group 2 has the least amount of microleakage and Group 5 has the most. Conclusion: Biodentine has excellent sealing capabilities and can be utilised to heal furcation perforations with or without internal matrix.

Platform adaptive trial of novel antivirals for early treatment of COVID-19 In the community (PANORAMIC): protocol for a randomised, controlled, open-label, adaptive platform trial of community novel antiviral treatment of COVID-19 in people at increased risk of more severe disease.

INTRODUCTION: There is an urgent need to determine the safety, effectiveness and cost-effectiveness of novel antiviral treatments for COVID-19 in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. METHODS AND ANALYSIS: PANORAMIC is a UK-wide, open-label, prospective, adaptive, multiarm platform, randomised clinical trial that evaluates antiviral treatments for COVID-19 in the community. A master protocol governs the addition of new antiviral treatments as they become available, and the introduction and cessation of existing interventions via interim analyses. The first two interventions to be evaluated are molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid). ELIGIBILITY CRITERIA: community-dwelling within 5 days of onset of symptomatic COVID-19 (confirmed by PCR or lateral flow test), and either (1) aged 50 years and over, or (2) aged 18-49 years with qualifying comorbidities. Registration occurs via the trial website and by telephone. Recruitment occurs remotely through the central trial team, or in person through clinical sites. Participants are randomised to receive either usual care or a trial drug plus usual care. Outcomes are collected via a participant-completed daily electronic symptom diary for 28 days post randomisation. Participants and/or their Trial Partner are contacted by the research team after days 7, 14 and 28 if the diary is not completed, or if the participant is unable to access the diary. The primary efficacy endpoint is all-cause, non-elective hospitalisation and/or death within 28 days of randomisation. Multiple prespecified interim analyses allow interventions to be stopped for futility or superiority based on prespecified decision criteria. A prospective economic evaluation is embedded within the trial. ETHICS AND DISSEMINATION: Ethical approval granted by South Central-Berkshire REC number: 21/SC/0393; IRAS project ID: 1004274. Results will be presented to policymakers and at conferences, and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN30448031; EudraCT number: 2021-005748-31.

Purification and characterization of a second type of neutral ceramidase from rat brain: a second more hydrophobic form of rat brain ceramidase.

Ceramidases (CDase) are enzymes that catalyze the hydrolysis of N-acyl linkage of ceramide (Cer) to generate sphingosine and free fatty acids. In this study we report the purification and characterization of a novel second type of neutral ceramidase from rat brain (RBCDase II). Triton X-100 protein extract from rat brain membrane was purified sequentially using Q-Sepharose, HiLoad16/60 Superdex 200pg, heparin-Sepharose, phenyl-Sepharose HP, and Mono Q columns. After Mono Q, the specific activity of the enzyme increased by ~15,000-fold over that of the rat brain homogenate. This enzyme has pH optima of 7.5, and it has a larger apparent molecular weight (110kDa) than the previously purified (90kDa) and characterized neutral rat brain CDase (RBCDase I). De-glycosylation experiments show that the differences in molecular mass of RBCDase I and II on SDS-PAGE are not due to the heterogeneity with N-glycan. RBCDase II is partially stimulated by Ca(2+) and is inhibited by pyrimidine mono nucleotides such as TMP and UMP. This finding is significant as it demonstrates for the first time an effect by nucleotides on a CDase activity. The enzyme was also inhibited by both oxidized and reduced GSH. The effects of metal ions were examined, and we found that the enzyme is very sensitive to Hg(2+) and Fe(3+), while it is not affected by Mn(2+). EDTA was somewhat inhibitory at a 20mM concentration.

A randomised trial of nicotine assisted reduction to stop in pharmacies - the RedPharm study.

BACKGROUND: Public policy and clinical treatment in tobacco addiction in the UK has focused on cessation: an abrupt attempt to stop all cigarettes. However, recent evidence suggests that allowing more gradual withdrawal from tobacco or even permanent partial substitution by nicotine replacement therapy (NRT) could lead to net benefits to public health. No jurisdiction has introduced smoking reduction programmes in normal clinical care and the best methods for their implementation is uncertain. Community pharmacists offering smoking cessation services in the UK are ideally placed to implement reduction programmes.This pilot study aims therefore to examine the feasibility of implementing smoking reduction programme in pharmacies, and also to see if behavioural support and a longer treatment affect the success rate for cessation. DESIGN AND METHODS: This is a 2 × 2 randomised factorial trial of behavioural support versus no support and short versus standard length reduction programme. The pharmacists will recruit 16 patients per pharmacy, 160 smokers altogether. Pharmacists will randomise each participant by sealed envelopes. In a standard supported programme, the pharmacist will give support for 34 weeks, inviting participants to set a treatment goal and providing advice on how to reduce cigarette use. Participants in the short programme will be given the same advice on how to reduce but will reduce smoking over four weeks. Participants in the no support arms will be given a leaflet that describes the reduction programmes in 4-week and 34-week format. All participants are encouraged to use of NRT to support the reduction. These processes will be measured by recording the number of recruited smokers; percentage of those who reduce and sustain their consumption to at least 50% of baseline value, and the proportion of people who attain 4 weeks abstinence and 6 months abstinence. Interviews will assess smokers' and pharmacists' views on the way the programme ran. DISCUSSION: This is a pilot study to assess the feasibility of offering smoking reduction programme within pharmacies that offer naturalistic setting to show population benefit from these programmes. Findings from this trial will inform the development of evidence-based treatment for smokers who want to reduce and best approaches to engage reluctant quitters onto the programme. TRIAL REGISTRATION: Current Controlled Trials ISRCTN 2010-019259-24.

Pharmacist-Assisted Varenicline Tobacco Cessation Treatment for Veterans.

Background: Pharmacists are uniquely positioned to provide tobacco cessation interventions given their medication expertise and accessibility to the public. The purpose of this study was to evaluate the efficacy and safety of management of varenicline by clinical pharmacy specialists (CPSs) compared with other clinicians. Methods: This retrospective chart review included patients with a varenicline prescription between July 1, 2019, and July 31, 2020. Primary outcomes were reduction in tobacco use at 12 weeks from baseline, continuous abstinence at 12 weeks, adherence to varenicline therapy, and time to first follow-up. For safety evaluation, charts were reviewed for documented adverse drug reactions. Results: Management by CPS compared with other clinicians was associated with similar mean (SD) reductions of tobacco use (-7.9 [10.4] vs -5.4 [9.8] cigarettes per day, respectively; P = .15) and rates of complete abstinence (34% vs 38%, respectively; P = .73) and higher adherence (42% vs 31%, respectively; P = .01). Mean (SD) time to first follow-up was shorter for patients in the CPS group: 52 (66) vs 163 (110) days; P < .001. Adverse events were more common in the CPS group compared with the other clinicians group (42% vs 23%; P = .02). Conclusions: These results suggest that CPS management of varenicline is as safe and effective as management by other clinicians. Additional research is needed to fully characterize the impact of pharmacist management of varenicline, justify expansion of CPS scope of practice, and ultimately enhance patient outcomes regarding tobacco cessation.

Public views of and reactions to the COVID-19 pandemic in England: a qualitative study with diverse ethnicities.

OBJECTIVES: To explore public reactions to the COVID-19 pandemic across diverse ethnic groups. DESIGN: Remote qualitative interviews and focus groups in English or Punjabi. Data were transcribed and analysed through inductive thematic analysis. SETTING: England and Wales, June to October 2020. PARTICIPANTS: 100 participants from 19 diverse 'self-identified' ethnic groups. RESULTS: Dismay, frustration and altruism were reported across all ethnic groups during the first 6-9 months of the COVID-19 pandemic. Dismay was caused by participants' reported individual, family and community risks, and loss of support networks. Frustration was caused by reported lack of recognition of the efforts of ethnic minority groups (EMGs), inaction by government to address COVID-19 and inequalities, rule breaking by government advisors, changing government rules around: border controls, personal protective equipment, social distancing, eating out, and perceived poor communication around COVID-19 and the Public Health England COVID-19 disparities report (leading to reported increased racism and social isolation). Altruism was felt by all, in the resilience of National Health Service (NHS) staff and their communities and families pulling together. Data, participants' suggested actions and the behaviour change wheel informed suggested interventions and policies to help control COVID-19. CONCLUSION: To improve trust and compliance future reports or guidance should clearly explain any stated differences in health outcomes by ethnicity or other risk group, including specific messages for these groups and concrete actions to minimise any risks. Messaging should reflect the uncertainty in data or advice and how guidance may change going forward as new evidence becomes available. A contingency plan is needed to mitigate the impact of COVID-19 across all communities including EMGs, the vulnerable and socially disadvantaged individuals, in preparation for any rise in cases and for future pandemics. Equality across ethnicities for healthcare is essential, and the NHS and local communities will need to be supported to attain this.

Attitudes towards coronavirus (COVID-19) vaccine and sources of information across diverse ethnic groups in the UK: a qualitative study from June to October 2020.

OBJECTIVES: Across diverse ethnic groups in the UK, explore attitudes and intentions towards COVID-19 vaccination and sources of COVID-19 information. DESIGN: Remote qualitative interviews and focus groups (FGs) conducted June-October 2020 before UK COVID-19 vaccine approval. Data were transcribed and analysed through inductive thematic analysis and mapped to the Theoretical Domains Framework. SETTING: England and Wales. PARTICIPANTS: 100 participants from 19 self-identified ethnic groups. RESULTS: Mistrust and doubt were reported across ethnic groups. Many participants shared concerns about perceived lack of information about COVID-19 vaccine safety and efficacy. There were differences within each ethnic group, with factors such as occupation and perceived health status influencing intention to accept a vaccine once made available. Across ethnic groups, participants believed that public contact occupations, older adults and vulnerable groups should be prioritised for vaccination. Perceived risk, social influences, occupation, age, comorbidities and engagement with healthcare influenced participants' intentions to accept vaccination once available. All Jewish FG participants intended to accept, while all Traveller FG participants indicated they probably would not.Facilitators to COVID-19 vaccine uptake across ethnic groups included: desire to return to normality and protect health and well-being; perceived higher risk of infection; evidence of vaccine safety and efficacy; vaccine availability and accessibility.COVID-19 information sources were influenced by social factors and included: friends and family; media and news outlets; research literature; and culture and religion. Participants across most different ethnic groups were concerned about misinformation or had negative attitudes towards the media. CONCLUSIONS: During vaccination rollout, including boosters, commissioners and providers should provide accurate information, authentic community outreach and use appropriate channels to disseminate information and counter misinformation. Adopting a context-specific approach to vaccine resources, interventions and policies and empowering communities has potential to increase trust in the programme.

Colchicine for COVID-19 in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial.

BACKGROUND: Colchicine has been proposed as a COVID-19 treatment. AIM: To determine whether colchicine reduces time to recovery and COVID-19-related admissions to hospital and/or deaths among people in the community. DESIGN AND SETTING: Prospective, multicentre, open-label, multi-arm, randomised, controlled, adaptive platform trial (PRINCIPLE). METHOD: Adults aged ≥65 years or ≥18 years with comorbidities or shortness of breath, and unwell for ≤14 days with suspected COVID-19 in the community, were randomised to usual care, usual care plus colchicine (500 µg daily for 14 days), or usual care plus other interventions. The co-primary endpoints were time to first self-reported recovery and admission to hospital/death related to COVID-19, within 28 days, analysed using Bayesian models. RESULTS: The trial opened on 2 April 2020. Randomisation to colchicine started on 4 March 2021 and stopped on 26 May 2021 because the prespecified time to recovery futility criterion was met. The primary analysis model included 2755 participants who were SARS-CoV-2 positive, randomised to colchicine (n = 156), usual care (n = 1145), and other treatments (n = 1454). Time to first self-reported recovery was similar in the colchicine group compared with usual care with an estimated hazard ratio of 0.92 (95% credible interval (CrI) = 0.72 to 1.16) and an estimated increase of 1.4 days in median time to self-reported recovery for colchicine versus usual care. The probability of meaningful benefit in time to recovery was very low at 1.8%. COVID-19-related admissions to hospital/deaths were similar in the colchicine group versus usual care, with an estimated odds ratio of 0.76 (95% CrI = 0.28 to 1.89) and an estimated difference of -0.4% (95% CrI = -2.7 to 2.4). CONCLUSION: Colchicine did not improve time to recovery in people at higher risk of complications with COVID-19 in the community.

Protein phosphatase 1-dependent dephosphorylation of Akt is the prime signaling event in sphingosine-induced apoptosis in Jurkat cells.

Sphingosine (SPH) is an important bioactive lipid involved in mediating a variety of cell functions including apoptosis. However, the signaling mechanism of SPH-induced apoptosis remains unclear. We have investigated whether SPH inhibits survival signaling in cells by inhibiting Akt kinase activity. This study demonstrates that treatment of Jurkat cells with SPH leads to Akt dephosphorylation as early as 15 min, and the cells undergo apoptosis after 6 h. This Akt dephosphorylation is not mediated through deactivation of upstream kinases, since SPH does not inhibit the upstream phosphoinositide-dependent kinase 1 (PDK1) phosphorylation. Rather, sensitivity to the Ser/Thr protein phosphatase inhibitors (calyculin A, phosphatidic acid, tautomycin, and okadaic acid) indicates an important role for protein phosphatase 1 (PP1) in this process. In vitro phosphatase assay, using Akt immunoprecipitate following treatment with SPH, reveals an increase in Akt-PP1 association as determined by immunoprecipitation analysis. Moreover, SPH-induced dephosphorylation of Akt at Ser(473) subsequently leads to the activation of GSK-3ß, caspase 3, PARP cleavage, and ultimately apoptosis. Pre-treatment with caspase 3 inhibitor z-VAD-fmk and Ser/Thr phosphatase inhibitor abrogates the effect of SPH on facilitating apoptosis. Altogether, these results demonstrate that PP1-mediated inhibition of the key anti-apoptotic protein, Akt, plays an important role in SPH-mediated apoptosis in Jurkat cells.

Glutathione selectively inhibits Doxorubicin induced phosphorylation of p53Ser¹5, caspase dependent ceramide production and apoptosis in human leukemic cells.

Glutathione (GSH) is the most abundant non-protein antioxidant in mammalian cells. It has been implicated in playing an important role in different signal transduction pathways, and its depletion is an early hallmark in the progression of apoptosis in response to a number of proapoptotic stimuli. We have selectively investigated the role of GSH in cytotoxic response of Jurkat and Molt-4 human leukemic cells to the anti-cancer drug Doxorubicin. In this study, we have shown that extracellular supplementation of GSH to human leukemic cells renders them a resistant phenotype to Doxorubicin treatment. Glutathione pre-treatment inhibits Doxorubicin-induced p53Ser(15) phosphorylation, caspase dependent ceramide (Cer) generation, Poly (ADP-ribose) polymerase (PARP) cleavage, and DNA fragmentation. Taken together, these results indicate that the major cellular antioxidant GSH influences the chemotherapeutic efficacy of Doxorubicin towards human leukemic cells.