Synthetic macrocyclic Ionophores

14-Crown-4 derivatives bearing either one or two oxymethyl, benzyl- oxymethyl, methoxycarbonylmethyl or carbamoylmethyl substituents have been prepared in an attempt to obtain selective ionophores for lithiumions. Complexation has been monitored by IR, (^13)C NMR, Fast Atom Bombardment Mass Spectrometry, and solvent polymeric membranes have been fabricated and evaluated using the fixed interference method. Improved lithium selectivities of the disubstituted 14-crown-4 ligands compared to the monosubstituted analogues in the potentiometric experiments, bears out the premise that there is a need to suppress competitive 2:1 complex formation with sodium. The most encouraging lithium selectivity was observed with an electrode based on trans- (2S,3S)(-)-2,3-bis(N,N'- dibutylcarbamoylmethyl)-1,4,8,11- tetraoxacyclo- tetradecane which vindicates the choice of axial amide donors to enhance the Li/Na selectivity of the 14-crown-4 skeleton. Triazacyclononane, triazacyclododecane and tetraazacyclododecane amide functionalised ligands were prepared in order to investigate the effect of donor number, macrocyclic ring size and chelate ring size on stability and selectivity of complexation with alkali and alkaline earth metal cations. Complexation has been monitored by IR, i3C NMR, Fast Atom Bombardment Mass Spectrometry and pH-metric titration experiments. The most stable complex was formed between calcium and N,N'-dimethyl- 1,4,7,10-tetraacetamido-1,4,7,10-tetraazacyclododecane, for which log K(CaL) =6.81 (H(_2)0). Once again, measurable log K values ≥ 3.9 in aqueous media for lithium, sodium and calcium complexation vindicate the choice of amide donors to ensure strong coordination with small cations of high charge density ratio

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

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

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

Scientific foundations for an IUCN Red List of ecosystems

No grant i

Contrasting pathways of environmental or biotic degradation and their corresponding risk classifications under criteria C and D.

<p>(a) initially widespread and benign degradation, later increasing in severity. (b) severity and extent of degradation increase at similar rates. (c) localised but severe degradation, later becoming more widespread. Ecosystems that just fail to meet the thresholds for Vulnerable status (e.g. extremely severe (>80%) decline in environmental quality over 20–30% of distribution, or severe (>30%) decline over 70–80% of distribution) may be assigned Near Threatened (NT) status.</p

Protocol for assessing the risk of collapse of an ecosystem using proposed Red List criteria v2.0 (see <b>Table 3</b><b>)</b>

<p>.</p

Number of ecosystems assessed for each criterion and number for which each criterion determined overall status.

<p>Number of ecosystems assessed for each criterion and number for which each criterion determined overall status.</p

Probability density functions for the population and ecosystem variables that measure proximity to the thresholds that define species extinction (A, B) and ecosystem collapse (C, D).

<p>The probability density functions represent uncertainty in the measurement of the variables. For species, the population threshold that defines extinction is known with certainty (e.g. zero abundance of a species, defined by the vertical line in A and B). In A, the estimated population is definitely greater than the extinction threshold, so there is no doubt that the species is extant. Alternatively, the probability that the abundance is above the threshold (the area under the curve) might be less than one (B), in which case the species could be extinct or extant. The shaded area is the probability that the species remains extant. For ecosystems, the x-axis could represent spatial distribution, number of species, water quality, etc. In contrast to species, uncertainty about the definition of ecosystem collapse leads to a range of possible values for this threshold (dashed box in C and D). The ecosystem variable is above this upper bound in some cases (C), so there is no doubt that the ecosystem persists. Alternatively, probable values for the ecosystem variable might intersect the uncertain threshold (D), in which case the ecosystem may be collapsed or not. In this case, there is some probability that the ecosystem parameter is above the upper bound of the threshold (shaded dark grey), which places a lower bound on the probability that the ecosystem persists (i.e. that it has not collapsed). There is an additional probability (pale grey) that the ecosystem parameter is above the threshold that depends on the amount of uncertainty in the threshold (i.e. width of the box). The sum of these two probabilities places an upper bound on the probability ecosystem persists. With further deterioration (E), the lower bound on the probability of ecosystem persistence is zero (no dark shading) and the upper bound is the pale shaded area.</p

Biotic and abiotic variables for assessing functional decline in the Aral Sea ecosystem, their reference values when the ecosystem was in a functional state (between 1911 and 1960) and bounded thresholds that define the collapsed state, assuming collapse occurred between 1976 and 1989.

<p>Data from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062111#pone.0062111-Micklin1" target="_blank">[78]</a>. Further details in Appendix 2.5).</p