EFFECTS OF SLEEP RESTRICTION AND RECOVERY ON THE CAPACITY OF GLUCOCORTICOIDS TO INHIBIT INFLAMMATORY MARKER EXPRESSION IN HUMAN MONOCYTES

Introduction: Chronic low-grade systemic inflammation is involved in the pathogenesis of many human diseases. Common sleep patterns of restricting sleep during weekdays and catching up on sleep over the weekend induce inflammatory upregulation that may not resolve following weekend recovery sleep. We hypothesize that this sleep pattern leads to an inflammatory imbalance of markers regulating inflammatory homeostasis, including inflammatory markers (eg, interleukin-6 (IL-6) and cyclooxygenase 2 (COX-2)) and markers of counter-inflammation (eg, glucocorticoids (GCs)). The enzyme COX-2 is involved in prostaglandin synthesis and is the target of pain-relieving nonsteroidal anti-inflammatory drugs (NSAIDs). GCs are used in the treatment of many inflammatory diseases, including severe acute infection with SARS-CoV-2. We investigated if sleep restriction impairs the capacity of GCs to inhibit inflammatory COX-2 expression in a preliminary dataset. Methods: The present preliminary dataset (N=6, 2F/4M) derives from an ongoing randomized controlled within-subjects trial consisting of three 11-day in-hospital protocols (2 restricted sleep arms, 1 control sleep arm). The ongoing study is blinded for administration of placebo or aspirin under sleep restriction. Under restricted sleep conditions, 2 nights of baseline sleep (8h/night) were followed by 5 nights of restricted sleep (4h/ night), concluding with 3 nights of recovery sleep (8h/night). In the control condition, participants could sleep 8h/night throughout the entire protocol. Blood samples were taken after baseline sleep, after 5 nights of restricted or control sleep, and after 2 nights of recovery sleep. Data were analyzed using generalized linear mixed models. Results: Sleep restriction was associated with decreased capacity of GCs to inhibit COX-2 expression in monocytes (p<.01) and has the expected inflammatory effect on IL-6 production in monocytes (p<.01). Moreover, sleep restriction has lasting inflammatory effects as shown in increased inflammation following 2 nights of recovery sleep (p<.01). Conclusion: In conclusion, the present preliminary analysis suggests that in patients treated with GCs, sleep restriction potentially reduces their effectiveness in controlling inflammation, thus contributing to increased inflammation-related morbidity. Sample collection and data analysis is ongoing.

COVID-19 pandemic: A Seismically Disruptive Environmental Event

After Second World War, the COVID-19 pandemic has caused so much losses to humankind that some countries have started it calling as a third world war or biological war, which has been imposed for reorganisation and dominance over world economy. The whole world has come to standstill and efforts of all the countries are concentrated to avoid extinction of human species. Most of the companies have come out with zero production in month of April, 2020. This paper explores the impact of this seismically disruptive environmental event on global environment and energy scenario. It provides a valuable guide to researchers, environmentalists and policy makers to provide a linkage between COVID-19 and various environmental concerns and remedial measures have also been suggested to combat SARS-CoV-2. Although the future trajectory of the pandemic remains uncertain, the pandemic has already brought many changes to how people live, and is likely to bring many more. As all the disasters have their time limits, one should be optimistic and must put all our feet together to win over this pandemic and respect the ecosystem before it is too late. © The Electrochemical Society

Perceived discrimination when using health-care services, health outcomes, and health-care utilisation among Romani people in Europe: evidence from the Second European Union Minorities and Discrimination Survey

BACKGROUND: The global COVID-19 pandemic has highlighted substantial health inequities in Europe. Minorities and immigrants are the populations most likely to experience disparities related to health-care access and health outcomes. We aimed to link self-reports of health conditions with experiences of discrimination when using health-care services among Romani ethnic minorities in the European Union (EU). METHODS: The Second EU Minorities and Discrimination Survey was disseminated in 2016 to ethnic minorities, immigrants, and descendants of immigrants in 19 member states of the EU (Austria, Belgium, Cyprus, Germany, Denmark, Greece, Spain, Finland, France, Ireland, Italy, Luxembourg, Malta, Netherlands, Poland, Portugal, Sweden, Slovenia, and the UK). The primary outcomes were self-reported health status (subjective assessment of own health conditions), health-care utilisation, and unmet health-care need. Experiences of discrimination when using health-care services in the past 5 years was the key explanatory variable. Anonymised data relating to perceived discrimination, self-reported good health, health-care utilisation, and socioeconomic status were available for individuals who identify as Romani ethnic minorities in nine EU member states-Bulgaria, Croatia, Czech Republic, Greece, Hungary, Portugal, Romania, Slovakia, and Spain. We used multivariate logistic regression analyses to examine the association between perceived discrimination and self-reported health status, health-care utilisation, and unmet health-care needs, controlled for sex, age, income level, education level, health insurance coverage, and residential location. Adjusted odds ratios (ORs) and 95% CIs of self-perceived discrimination are reported. FINDINGS: Using data on perceived discrimination when using health care, self-reported health status, health-care access, and socioeconomic status for 7942 Romani individuals (aged 16-90 years), including 4046 Romani individuals who have used health-care services during the past 5 years, we found that perceived discrimination when utilising health care is more prevalent for Romani people than other ethnic minorities in Europe (OR 2·19, 95% CI 1·96-2·44). After controlling for sex, age, income level, education level, health insurance coverage, and residential location, our multivariate logistic regression analyses showed that the perceived discrimination of Romani people is negatively associated with self-reported good health (adjusted OR 0·84, 0·69-1·03), and health-care utilisation (adjusted OR 0·34, 0·25-0·44). Furthermore, Romani people's perceived discrimination is associated with an increased risk of unmet health-care needs (adjusted OR 3·01, 2·27-3·98). The results were robust across sexes. INTERPRETATION: A multifaceted strategy might be needed to eliminate the disparities in health outcomes and health-care access between the Romani ethnic group and other ethnic minority groups in the EU, including expanding access to health care, addressing social determinants of health, and advancing anti-discrimination regulations in the EU. FUNDING: None.

Efficacy of convalescent plasma in the treatment of coronavirus disease 2019: a systematic review

Objective To systematically review the efficacy of convalescent plasma (CP) in the treatment of coronavirus disease 2019 (COVID-19). Methods PubMed, EMbase, The Cochrane Library, VIP, WanFang Data and CNKI databases were electronically searched to collect randomized controlled trials (RCTs) on the efficacy of CP in the treatment of COVID-19 from inception to September 15th, 2021. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies;then, meta-analysis was performed using RevMan 5.4.1 software. Results A total of 16 RCTs involving 15 301 patients were included. The results of meta-analysis showed that CP treatment did not reduce mortality compared with no-placebo (RR=0.99, 95%CI 0.93 to 1.05, P=0.63) or normal saline (RR=1.06, 95%CI 0.60 to 1.86, P=0.84). However, compared with standard plasma, the mortality of CP group was lower (RR=0.59, 95%CI 0.37 to 0.95, P=0.03). In addition, compared with no-placebo or normal saline, CP treatment could not improve the clinical condition at 28-30 days, reduce mortality at early treatment and in patients without invasive mechanical ventilation when randomized. Conclusion Current evidence shows that compared with no-placebo or normal saline, CP does not reduce mortality in patients with COVID-19. However, when the disease progresses to the point where standard plasma is required, CP may reduce mortality. In addition, use of CP in patients with early or noncritical COVID-19 failed to reduce mortality. Due to limited quality and quantity of the included studies, more high-quality studies are required to verify the above conclusion. © 2022 West China University of Medical Science. All rights reserved.

Venetoclax with Azacitidine or Low Dose Cytarabine As an Alternative to Intensive Chemotherapy in Fit Adults during the COVID19 Pandemic: Real World Data from the UK National Health Service

Background Based on early evidence of a high rate of coronavirus mortality in patients with acute myeloid leukaemia (AML) undergoing intensive chemotherapy (IC), the national health service (NHS) in the United Kingdom temporarily made venetoclax available as an alternative therapy, with the aim of reducing both mortality and healthcare resource use. From late April 2020, venetoclax was available to patients aged >16y with NPM1 mutation without FLT3 internal tandem duplication (ITD), patients aged >50y with NPM1, IDH1 or IDH2 mutations (regardless of FLT3 status) and patients aged >60y without favourable-risk cytogenetics. Venetoclax could be given with either azacitidine or low-dose cytarabine (LDAC), with the latter recommended mainly for patients with NPM1 mutation. We report a health-system-wide real world data collection for toxicity and patient outcomes across 65 NHS Hospitals. Methods Each patient was registered on a central NHS database. Clinicians certified that their patient met the above criteria, had not received previous AML treatment, and was fit for induction chemotherapy. Anonymised data were retrospectively collected by treating physicians. Venetoclax dose, duration and toxicity information was requested for the first 4 cycles of therapy. Response definitions were as per European Leukaemia Network (ELN) guidelines. A total of 870 patients have been registered on the scheme, with outcomes reported here for those with follow-up information at a data cut on 1st August 2021. Results There were 301 patients, median age 72y (range 34 - 90) with 62% male. The majority (81%) had an ECOG performance status of 0-1. AML was secondary to a previous haematological disorder in 33%, therapy-related in 10% and de novo in the remaining 57%. MRC cytogenetic risk was intermediate in 70% and adverse in 27%. NPM1 mutations were detected in 28% and FLT3-ITD in 12%. Next-generation sequencing results were available in 86% of patients, which detected mutations in IDH1 or IDH2 in 28%, ASXL1 in 20%, RUNX1 in 17% and TP53 in 12%. The ELN risk was favourable for 23%, intermediate for 30% and adverse for 44%. A majority received venetoclax in combination with azacitidine (85%), with the remaining 15% receiving LDAC. The LDAC cohort was enriched for de novo AML (76% vs 54%) and NPM1-mutated disease (56% vs 23%). Most patients (81%) followed the recommended initial schedule of venetoclax 100mg daily for 28 days in combination with posaconazole or voriconazole. Patients spent a median 14 days in hospital in cycle 1, then a median of 0 days for cycles 2-4. In cycles 1, 2, 3 and 4, the median number of days for recovery of neutrophils to >0.5x10 9/L was 33, 25, 24 and 14 respectively, and the median number of days to recovery of platelets to >50x10 9/L was 22, 3, 0 (no drop below 50) and 0. The composite complete remission (CR) / CR with incomplete haematological recovery (CRi) rate was 70%. MRD data is being collected. The best response was morphological leukaemia free state (MLFS) in 2%, partial remission in 7% and refractory disease in 11%. CR/CRi was higher in de novo (78%) compared to secondary AML (57%, p=0.02);NPM1 mutated (78% vs 67%, p=0.02) and IDH1/IDH2 mutated disease (85% vs 62%, p=0.02). ELN favourable risk patients had the highest CR/CRi rate (85%, intermediate 71%, adverse 60%, p=0.01). Median follow-up was 8.2 months (95%CI 7.8 - 9.0) with median overall survival (OS) 12.8 months (95%CI 10.9 - not reached). Mortality at day 30 was 5.7% and day 60 was 8.4%. 12-month overall survival was 51%, increasing to 71% in those who achieved CR/CRi. Survival was poorer in secondary (HR 1.9, p <0.01) and therapy-related AML (HR 2.1, p=0.02), better in NPM1 mutated (HR 0.6, p=0.02) and IDH mutated (HR 0.5, p=0.02) disease and poorer with TP53 mutation (HR 2.0, p=0.01). Overall survival did not differ for patients treated with LDAC compared to azacitidine (HR 1.1, p=0.7). Conclusion This large real-world study demonstrates CR/CRi and survival rates comparable to those reported in prospective clinical trials. Importantly, during t e COVID-19 pandemic, the adoption of venetoclax regimens permitted the great majority of treatment to be delivered as an outpatient with significant resource saving at a time of critically constrained inpatient resources. The data support prospective comparisons of venetoclax-based regimens to IC in fit adults with AML particularly in older patients with de novo AML, NPM1-mutated and IDH-mutated disease. [Formula presented] Disclosures: Belsham: Celgene: Other: meeting attendance;Abbvie: Other: meeting attendance. Khan: Abbvie: Honoraria;Astellas: Honoraria;Takeda: Honoraria;Jazz: Honoraria;Gilead: Honoraria;Novartis: Honoraria. Khwaja: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Latif: Kite: Consultancy, Honoraria, Speakers Bureau;Jazz: Consultancy, Honoraria;Daiichi Sankyo: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Amgen: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Astellas: Consultancy, Honoraria, Speakers Bureau;Takeda UK: Speakers Bureau. Loke: Pfizer: Honoraria;Amgen: Honoraria;Janssen: Honoraria;Novartis: Other: Travel;Daichi Sankyo: Other: Travel. Murthy: Abbvie: Other: support to attend educational conferences. Smith: ARIAD: Honoraria;Pfizer: Speakers Bureau;Daiichi Sankyo: Speakers Bureau. Whitmill: Daiichi-sankyo: Other: travel fees;EHA in stockholm: Other: conference support. Craddock: Novartis Pharmaceuticals: Other: Advisory Board;Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dillon: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Jazz: Other: Education events;Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events;Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau;Menarini: Membership on an entity's Board of Directors or advisory committees;Astellas: Consultancy, Other: Educational Events, Speakers Bureau;Amgen: Other: Research support (paid to institution);Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events.

Gilteritinib for Relapsed Acute Myeloid Leukaemia with FLT3 Mutation during the COVID-19 Pandemic: Real World Experience from the UK National Health Service

Background Early data suggest that patients undergoing salvage chemotherapy for relapsed or refractory (R/R) acute myeloid leukaemia (AML) have poor outcomes if infected with SARS-CoV-2, and nosocomial transmission has been a major problem worldwide. Gilteritinib is effective in R/R FLT3 mutated AML, is significantly less immunosuppressive and does not require hospital admission, however at the start of the pandemic this was not yet approved for routine use in all countries. In the United Kingdom, the National Health Service (NHS) made gilteritinib available as an emergency measure from late April 2020 to patients aged >16y with R/R FLT3 mutated AML, with the aim of reducing both mortality and healthcare resource use. We report a health-system-wide real world data collection for toxicity and patient outcomes across 27 NHS Hospitals. Methods Each patient was registered on a central NHS database, with clinicians certifying that their patient met the above criteria. Anonymised data were retrospectively collected by treating physicians. Gilteritinib dose, duration and toxicity information was requested for the first 4 cycles of therapy. Response definitions were as per European Leukaemia Network (ELN) guidelines. A total of 81 patients have been registered on the scheme, with outcomes reported here for those with follow-up information at a data cut on 1st August 2021. Results Fifty patients were included with a median age of 59y (range 19 - 77) and 50% male. The majority (83%) had an ECOG performance status of 0-1. AML was secondary to a previous haematological disorder in 12%, therapy-related in 4% and de novo in the remaining 84%. The disease was refractory to the last therapy in 38%. Most patients had previously received 1 (65%) or 2 (33%) lines of therapy, including intensive chemotherapy in a majority (86%). A FLT3 inhibitor had previously been administered to 45% and 35% were post allogeneic transplant. The FLT3 mutation was an internal tandem duplication (ITD) in 80% and tyrosine kinase domain (TKD) mutation in 22%. NPM1 mutations were detected in 34%. Next-generation sequencing results were available for 94% of patients, with mutations in IDH1 or IDH2 in 12.5%, ASXL1 in 2%, RUNX1 in 21% and no TP53 mutations. Patients spent a median 3.5 days in hospital in cycle 1, 0 days in cycles 2 and 3 and 1 day in cycle 4. In cycles 1, 2, 3 and 4, the median number of days of grade 4 neutropenia was 18, 7, 7.5, and 6.5 respectively, and the grade 4 thrombocytopenia was 2, 7, 0.5 and 0.5. The composite complete remission (CR) / CR with incomplete haematological recovery (CRi) rate was 27%. MRD data is being collected. The best response was morphological leukaemia free state (MLFS) in 4%, partial remission (PR) in 25% and refractory disease in 38%. The rate of combined CR/CRi did not differ in those with previous exposure to FLT3 inhibitors (23% vs 32%, p=0.6) or with past allogeneic transplant (29% vs 27%, p=0.3). There were no CR/CRi in patients with adverse cytogenetic risk. Median follow-up was 10.5 months (95%CI 7.3 - 12.3) with median overall survival (OS) 6.7 months (95%CI 4.5 - not reached). Mortality at day 30 was 0% and day 60 was 14%. 12-month overall survival was 38%. Patients who achieved a CR/CRi had a 12-month OS of 83%, and for PR this was 35%. Survival did not differ in those with previous FLT3 inhibitor exposure (HR 1.0, p>0.9) or allogeneic transplant (HR 0.63, p=0.3). Seven patients (14%) so far have been bridged with gilteritinib to allogeneic transplant. Conclusion Our data demonstrate that gilteritinib is well tolerated and clinically active in adults with relapsed FLT3 mutated AML. Importantly, during the COVID-19 pandemic, its availability has permitted the great majority of treatment to be delivered as an outpatient with significant resource saving at a time of critically constrained inpatient resources. Patients who achieve CR/CRi have good short-term outcomes and are able to proceed to a potentially curative allogeneic stem cell transplant. [Formula presented] Disclosures: Belsham: Celgene: Other: meeting attendance;Abbvie: Other: meeting attendance. Byrne: Incyte: Honoraria. Khan: Abbvie: Honoraria;Astellas: Honoraria;Takeda: Honoraria;Jazz: Honoraria;Gilead: Honoraria;Novartis: Honoraria. Khwaja: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Astellas: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Latif: Kite: Consultancy, Honoraria, Speakers Bureau;Jazz: Consultancy, Honoraria;Daiichi Sankyo: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Amgen: Consultancy, Honoraria;Abbvie: Consultancy, Honoraria;Astellas: Consultancy, Honoraria, Speakers Bureau;Takeda UK: Speakers Bureau. Loke: Amgen: Honoraria;Daichi Sankyo: Other: Travel Support;Janssen: Honoraria;Novartis: Other: Travel Support;Pfizer: Honoraria. Munisamy: Jazz Pharmaceuticals: Speakers Bureau;Roche: Speakers Bureau. Murthy: Abbvie: Other: support to attend educational conferences. Smith: Daiichi Sankyo: Speakers Bureau;Pfizer: Speakers Bureau;ARIAD: Honoraria. Craddock: Novartis Pharmaceuticals: Other: Advisory Board;Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dillon: Amgen: Other: Research support (paid to institution);Astellas: Consultancy, Other: Educational Events, Speakers Bureau;Menarini: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau;Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events;Jazz: Other: Education events;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events.