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Health outcomes 3 months and 6 months after molnupiravir treatment for COVID-19 for people at higher risk in the community (PANORAMIC):a randomised controlled trial
No full textBackgroundNo randomised controlled trials have yet reported on the effectiveness of molnupiravir on longer term outcomes for COVID-19. The PANORAMIC trial found molnupiravir reduced time to recovery in acute COVID-19 over 28 days. We aimed to report the effect of molnupiravir treatment for COVID-19 on wellbeing, severe and persistent symptoms, new infections, health care and social service use, medication use, and time off work at 3 months and 6 months post-randomisation.MethodsThis study is a follow-up to the main analysis, which was based on the first 28 days of follow-up and has been previously reported. For this multicentre, primary care, open-label, multi-arm, prospective randomised controlled trial conducted in the UK, participants were eligible if aged at least 50 years, or at least 18 years with a comorbidity, and unwell 5 days or less with confirmed COVID-19 in the community. Participants were randomly assigned to the usual care group or molnupiravir group plus usual care (800 mg twice a day for 5 days), which was stratified by age (<50 years or ≥50 years) and vaccination status (at least one dose: yes or no). The primary outcome was hospitalisation or death (or both) at 28 days; all longer term outcomes were considered to be secondary outcomes and included self-reported ratings of wellness (on a scale of 0–10), experiencing any symptom (fever, cough, shortness of breath, fatigue, muscle ache, nausea and vomiting, diarrhoea, loss of smell or taste, headache, dizziness, abdominal pain, and generally feeling unwell) rated as severe (moderately bad or major problem) or persistent, any health and social care use, health-related quality of life (measured by the EQ-5D-5L), time off work or school, new infections, and hospitalisation.FindingsBetween Dec 8, 2021, and April 27, 2022, 25 783 participants were randomly assigned to the molnupiravir plus usual care group (n=12 821) or usual care group (n=12 962). Long-term follow-up data were available for 23 008 (89·2%) of 25 784 participants with 11 778 (91·9%) of 12 821 participants in the molnupiravir plus usual care group and 11 230 (86·6%) of 12 963 in the usual care group. 22 806 (99·1%) of 23 008 had at least one previous dose of a SARS-CoV-2 vaccine. Any severe (3 months: adjusted risk difference –1·6% [–2·6% to –0·6%]; probability superiority [p(sup)]>0·99; number needed to treat [NNT] 62·5; 6 months: –1·9% [–2·9% to –0·9%]; p(sup)>0·99, NNT 52·6) or persistent symptoms (3 months: adjusted risk difference –2·1% [–2·9% to –1·5%]; p(sup)>0·99; NNT 47·6; 6 months: –2·5% [–3·3% to –1·6%]; p(sup)>0·99; NNT 40) were reduced in severity, and health-related quality of life (measured by the EQ-5D-5L) improved in the molnupiravir plus usual care group at 3 months and 6 months (3 months: adjusted mean difference 1·08 [0·65 to 1·53]; p(sup)>0·99; 6 months: 1·09 [0·63 to 1·55]; p(sup)>0·99). Ratings of wellness (3 months: adjusted mean difference 0·15 (0·11 to 0·19); p(sup)>0·99; 6 months: 0·12 (0·07 to 0·16); p(sup)>0·99), experiencing any more severe symptom (3 months; adjusted risk difference –1·6% [–2·6% to –0·6%]; p(sup)=0·99; 6 months: –1·9% [–2·9% to –0·9%]; p(sup)>0·99), and health-care use (3 months: adjusted risk difference –1·4% [–2·3% to –0·4%]; p(sup)>0·99; NNT 71·4; 6 months: –0·5% [–1·5% to 0·4%]; p(sup)>0·99; NNT 200) had high probabilities of superiority with molnupiravir treatment. There were significant differences in persistence of any symptom (910 [8·9%] of 10 190 vs 1027 [11%] of 9332, NNT 67) at 6 months, and reported time off work at 3 months (2017 [17·9%] of 11 274 vs 2385 [22·4%] of 10 628) and 6 months (460 [4·4%] of 10 562 vs 527 [5·4%] of 9846; NNT 100). There were no differences in hospitalisations at long-term follow-up.InterpretationIn a vaccinated population, people treated with molnupiravir for acute COVID-19 felt better, experienced fewer and less severe COVID-19 associated symptoms, accessed health care less often, and took less time off work at 6 months. However, the absolute differences in this open-label design are small with high numbers needed to treat.</div
Writing for justice, reading for absence
No full textConversing with Laura Shepherd in The Self and Other Stories, this essay considers accompaniment, embodiment, expertise, and representation through a care-infused lens. I present my readings of contentions in her book, and ask what it means to view position, power, and presence in writing. Through my reading, I present Shepherd’s vulnerability as a mode of writing justice, despite its absences
Quantum backreaction effect in optical solitons
No full textOptical solitons classically are stationary solutions of the nonlinear Schrödinger equation. We perform a quantum field theoretic treatment by quantising a linearised fluctuation field around the classical soliton solution which can be seen as providing a background spacetime for the field. The linearised fluctuation modifies the soliton background, which is often neglected, reminiscent of the nondepleted-pump approximation. Going beyond this approximation and by using a number-conserving Bogoliubov approach, we find unstable modes that grow as the soliton propagates. Eventually, these unstable modes induce a considerable (backreaction) effect in the soliton. We calculate the backreaction in the classical field fully analytically in the leading second order. The result is a quadratic local decrease of the soliton photon number in propagation due to the backreaction effect of the unstable mode. Provided the initial pulse is close to the classical soliton solution, the unstable mode contributions always become dominant. We also consider practical scenarios for observing this quantum-induced soliton distortion, in the spectral domain. The backreaction, which we expect to be present in bright and dark, discrete and continuous solitons and other nonlinear pulses plays an important role in future optical analogue gravity experiments, for soliton lasers, and optical communications
Competitive behaviors in <i>Serratia marcescens</i> are coordinately regulated by a lifestyle switch frequently inactivated in the clinical environment
No full textOpportunistic bacterial pathogens must compete with other bacteria and switch between host- and environment-adapted states. Type VI secretion systems (T6SSs) occur widely in gram-negative bacteria and can efficiently kill neighboring competitors. We determined the distribution of T6SSs across the genus Serratia and observed that a highly conserved antibacterial T6SS is differentially active between closely related clinical isolates of Serratia marcescens. By combining genomic and experimental approaches, we identified a genus-core two-component system, BetR-Reg1-Reg2, that controls T6SS activity and exhibits frequent inactivating mutations, exclusively in S. marcescens isolates of clinical origin. This regulatory system controls a number of lifestyle-related traits at transcriptional and post-translational levels, including T6SS activity, antibiotic production, motility, and adhesion, with loss of BetR increasing virulence in an in vivo infection model. Our data support a model whereby this system represents a conserved, modular switch from sessile to pioneering and aggressive behavior, which is subject to selection pressure in clinical environments
Five year mortality in an RCT of a lung cancer biomarker to select people for low dose CT screening
No full textThe role of biomarkers in risk-based early detection of lung cancer may enable screening to become cost effective and widely accessible. EarlyCDT-Lung is an example of such a blood-based autoantibody biomarker which may improve accessibility to Low dose Computed Tomography (LDCT) screening for those at highest risk. We randomized 12 208 individuals aged 50–75 at high risk of developing lung cancer to either the test or to standard clinical care. Outcomes were ascertained from Register of Deaths and Cancer Registry. Cox proportional hazards models were used to estimate the hazard ratio of the rate of deaths from all causes and lung cancer. Additional analyses were performed for cases of lung cancer diagnosed within two years of the initial test. After 5 years 326 lung cancers were detected (2.7% of those enrolled). The total number of deaths reported from all causes in the intervention group was 344 compared to 388 in the control group. There were 73 lung cancer deaths in the intervention arm and 90 in the controls (Adjusted HR 0.789 (0.636, 0.978). An analysis of cases of lung cancer detected within 2 years of randomization in the intervention group showed that there were 34 deaths from all causes and 29 from lung cancer. In the control group there were 56 deaths with 49 from lung cancer. In those diagnosed with lung cancer within 2 years of randomization the hazard ratio for all cause mortality was 0.615 (0.401,0.942) and for lung cancer 0.598 (0.378, 0.946). Further large-scale studies of the role of biomarkers to target lung cancer screening, in addition to LDCT, are likely to provide additional value
A trichotomy for hitting times and escape rates for a class of unimodal maps
No full textWe consider local escape rates and hitting time statistics for unimodal interval maps of Misiurewicz–Thurston type. We prove that for any point z in the interval, there is a local escape rate and hitting time statistics that is one of three types. While it is key that we cover all points z, the particular interest here is when z is periodic and in the postcritical orbit that yields the third part of the trichotomy. We also prove generalized asymptotic escape rates of the form first shown by Bruin, Demers and Todd
Generation of iterated wreath products constructed from alternating, symmetric and cyclic groups
No full textLet G1, G2, … be a sequence of groups each of which is either an alternating group, a symmetric group or a cyclic group. Let us construct a sequence (Wi) of wreath products via W1 = G1 and, for each i ≥ 1, Wi+1 = Gi+1 wr Wi via the natural permutation action. We determine the minimum number d(Wi) of generators required for each wreath product in this sequence
Myanmar 2024:whose tide has turned?
No full textThis article highlights the multi-scalar politics of Myanmar, where regional politics and geopolitics interact with and compound national and local issues and conflicts. The first part of 2024 confirmed the trends of the previous year. Ethnic armed organizations (EAOs), in coalition or individually, capitalized on the momentum offered by Operation 1027 with the members of the 3 Brotherhood Alliance gaining ground in Rakhine and Shan States, until a China-brokered ceasefire in January formalized a military withdrawal from key towns and strategic roads. The same groups embarked on ‘Part II’ of Operation 1027 in late June and July, making additional important gains, as evidenced by the capture of the strategic town of Lashio in Shan State and additional territorial gains by the Arakan Army (AA) in Rakhine State. The AA expanded its control of the State further and by the end of the year it had expelled the Myanmar Armed Forces (MAF, the junta’s military) from most of the state. The junta appeared incapable of taking the strategic or even operational initiative and was under attack from all fronts. It lost control of most of its land borders. Perhaps for the first time since independence, it became possible to think of a defeat of the Myanmar military. And yet, over the summer, the anti-military tide in Shan State came to a halt. Feeling that some EAOs had simply gone «too far» and that a collapse of the junta and – by extension – of the state was conceivable, China changed its policy, extending greater support to the junta and withdrawing support from some of its closest EAOs, even arresting its leaders on Chinese territory. Inter-EAO conflicts ensued in Shan State, favouring the military’s position there. Throughout the year, the regime remained embattled, suffering a growing number of defeats, but was not on the verge of imminent collapse
Faster adaptation but slower divergence of X chromosomes under paternal genome elimination
No full textDifferences in transmission and ploidy between sex chromosomes and autosomes drive divergent evolutionary trajectories, with sex chromosomes generally evolving faster. Because sex-linked genes are transmitted less frequently, they are under less efficient selection. Conversely, exposure of recessive mutations on haploid sex chromosomes creates more efficient selection. In most systems, these effects occur simultaneously and are confounded. The fly families Sciaridae (fungus gnats) and Cecidomyiidae (gall midges) have X0 sex determination, but males transmit only maternally inherited chromosomes. This phenomenon results in equal transmission of the X and autosomes, allowing the effect of haploid selection to be studied in isolation. We discover that, unlike well-studied systems, X chromosomes diverge more slowly than autosomes in these flies. Using population genomic and expression data, we show that despite the X evolving more adaptively, stronger purifying selection explains slower divergence. Our findings demonstrate the utility of non-Mendelian inheritance systems for understanding fundamental evolutionary processes
Square array designs for unreplicated test treatments with replicated controls
No full textThis paper is about the construction of augmented row–column designs for unreplicated trials. The method uses the representation of a k × t equireplicate incomplete-block design with t treatments in t blocks of size k, termed an auxiliary block design, as a t × t square array design with k controls, where k < t. This can be regarded as an extension of the representation of a Youden square as a partial Latin square for unreplicated trials. Properties of the designs, in particular in relation to connectedness and randomization, are explored. Particular attention is given to square array designs which minimize the average variances of the estimates of paired comparisons between test lines and controls and between test line and test line effects. The use of equireplicate cyclic designs as auxiliary block designs is highlighted. These provide a flexible and workable family of augmented row–column square array designs. Designs whose auxiliary block designs are not cyclic are also covered