Leaders do not look back, or do they?

We study the effect of adding to a directed chain of interconnected systems a directed feedback from the last element in the chain to the first. The problem is closely related to the fundamental question of how a change in network topology may influence the behavior of coupled systems. We begin the analysis by investigating a simple linear system. The matrix that specifies the system dynamics is the transpose of the network Laplacian matrix, which codes the connectivity of the network. Our analysis shows that for any nonzero complex eigenvalue $\lambda$ of this matrix, the following inequality holds: $\frac{|\Im \lambda |}{|\Re \lambda |} \leq \cot\frac{\pi}{n}$. This bound is sharp, as it becomes an equality for an eigenvalue of a simple directed cycle with uniform interaction weights. The latter has the slowest decay of oscillations among all other network configurations with the same number of states. The result is generalized to directed rings and chains of identical nonlinear oscillators. For directed rings, a lower bound $\sigma_c$ for the connection strengths that guarantees asymptotic synchronization is found to follow a similar pattern: $\sigma_c=\frac{1}{1-\cos\left( 2\pi /n\right)}$. Numerical analysis revealed that, depending on the network size $n$, multiple dynamic regimes co-exist in the state space of the system. In addition to the fully synchronous state a rotating wave solution occurs. The effect is observed in networks exceeding a certain critical size. The emergence of a rotating wave highlights the importance of long chains and loops in networks of oscillators: the larger the size of chains and loops, the more sensitive the network dynamics becomes to removal or addition of a single connection

Going it alone: health and Brexit in the UK

When the UK left the single market, it marked the end of the application of European law and institutions which underpinned many elements of health and health care in the UK. Regulations on medicines and devices, laws on the buying and selling of care, trade agreements, and rules on migration which had previously worked across most of a continent, were repatriated to the UK. This report, an interim output from the Health and International Relations Monitor project funded by the Health Foundation, considers the impact of leaving the EU and changing international relations for health. It considers changes in health across six key areas: medicines and devices, international trade agreements, devolution, procurement, workforce and Northern Ireland. In the full report to be published in the Spring, we intend to examine two of the building blocks of health most affected by Brexit - workforce and living standards

Adherence to antiparkinsonian medication: An in-depth qualitative study

Background: Adherence to prescribed medication is low. It is a major problem as following practitioners’ recommendations is strongly associated with good patient outcomes. Little research has been undertaken with people in the early stages of Parkinson's disease although achieving symptom control depends on regularly timing doses. Research questions: How do people with Parkinson's disease adhere to prescribed medication, and what are the antecedents of non-adherence to antiparkinsonian medication? Design: Exploratory qualitative study using semi-structured interviews. Setting: Specialist Parkinson's disease clinic in one National Health Service hospital in England. Participants: Fifteen consecutive patients not yet in the advanced stages of Parkinson's disease living at home and responsible for managing their own medication or managing medication with the help of their carer. Methods: Semi-structured interviews with open questions. Findings: Each respondent demonstrated at least one type and in most cases several different types of non-adherent behaviour. Inadvertent minor non-adherence occurred because patients forgot to take tablets or muddled doses. Minor deliberate deviations occurred when patients took occasional extra tablets or brought forward doses to achieve better symptom control, often to cater for situations that were anticipated as especially demanding. Deliberate major non-adherence was very common and always related to over-use of medication. The experiences of parkinsonism were particular to the individual. The specific circumstances that prompted an episode of non-adherence varied between patients. Nevertheless there was evidence of negotiation between respondents and the Parkinson's disease nurse specialist; medication regimes were altered in conjunction with the patient during formal consultations and by telephone. Conclusion: Non-adherence to prescribed medication for people with chronic conditions is complex and for people with Parkinson's disease it was possible to identify different types of non-adherence. The possible existence of a typology of non-adherence for people with other chronic conditions merits investigation. Further research is needed to establish whether the findings of this small scale qualitative study can be replicated with a larger, more representative sample and establish how people with Parkinson's disease might be encouraged to adhere to medication regimes to improve symptom control

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The utility of lung ultrasound in COVID-19:A systematic scoping review

Introduction: Lung ultrasound (LUS) has an established evidence base and has proven useful in previous viral epidemics. An understanding of the utility of LUS in COVID-19 is crucial to determine its most suitable role based on local circumstances. Method: Online databases, specialist websites and social media platforms were searched to identify studies that explore the utility of LUS in COVID-19. Case reports and recommendations were excluded. Findings: In total, 33 studies were identified which represent a rapidly expanding evidence base for LUS in COVID-19. The quality of the included studies was relatively low; however, LUS certainly appears to be a highly sensitive and fairly specific test for COVID-19 in all ages and in pregnancy. Discussion: There may be LUS findings and patterns that are relatively specific to COVID-19; however, specificity may also be influenced by factors such as disease severity, pre-existing lung disease, operator experience, disease prevalence and the reference standard. Conclusion: LUS is almost certainly more sensitive than chest radiograph for COVID-19 and has several advantages over computed tomography and real-time polymerase chain reaction. High-quality research is needed into various aspects of LUS including: diagnostic accuracy in undifferentiated patients; triage and prognostication; monitoring progression and guiding interventions; the persistence of residual LUS findings; inter-observer agreement and the role of contrast-enhanced LUS.</p