Safety, Efficacy and Pharmacokinetics of AZD7442 (Tixagevimab/Cilgavimab) for Treatment of Mild-to-Moderate COVID-19: 15-Month Final Analysis of the TACKLE Trial

Introduction: In the phase 3 TACKLE study, outpatient treatment with AZD7442 (tixagevimab/cilgavimab) was well tolerated and significantly reduced progression to severe disease or death through day 29 in adults with mild-to-moderate coronavirus disease 2019 (COVID-19) at the primary analysis. Here, we report data from the final analysis of the TACKLE study, performed after approximately 15 months’ follow-up. Methods: Eligible participants were randomized 1:1 and dosed within 7 days of symptom onset with 600 mg intramuscular AZD7442 (n = 456; 300 mg tixagevimab/300 mg cilgavimab) or placebo (n = 454). Results: Severe COVID-19 or death through day 29 occurred in 4.4% and 8.8% of participants who received AZD7442 or placebo, a relative risk reduction (RRR) of 50.4% [95% confidence interval (CI) 14.4, 71.3; p = 0.0096]; among participants dosed within 5 days of symptom onset, the RRR was 66.9% (95% CI 31.1, 84.1; p = 0.002). Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 occurred in 5.0% of participants receiving AZD7442 versus 9.7% receiving placebo, an RRR of 49.2% (95% CI 14.7, 69.8; p = 0.009). Adverse events occurred in 55.5% and 55.9% of participants who received AZD7442 or placebo, respectively, and were mostly mild or moderate in severity. Serious adverse events occurred in 10.2% and 14.4% of participants who received AZD7442 or placebo, respectively, and deaths occurred in 1.8% of participants in both groups. Serum concentration–time profiles recorded over 457 days were similar for AZD7442, tixagevimab, and cilgavimab, and were consistent with the extended half-life reported for AZD7442 (approx. 90 days). Conclusions: AZD7442 reduced the risk of progression to severe COVID-19, hospitalization, and death, was well tolerated through 15 months, and exhibited predictable pharmacokinetics in outpatients with mild-to-moderate COVID-19. These data support the long-term safety of using long-acting monoclonal antibodies to treat COVID-19. Trial Registration: Clinicaltrials.gov, NCT04723394. (https://clinicaltrials.gov/study/NCT04723394

Transplanting the leafy liverwort Herbertus hutchinsiae : A suitable conservation tool to maintain oceanic-montane liverwort-rich heath?

Thanks to the relevant landowners and managers for permission to carry out the experiments, Chris Preston for helping to obtain the liverwort distribution records and the distribution map, Gordon Rothero and Dave Horsfield for advice on choosing experimental sites and Alex Douglas for statistical advice. Juliane Geyer’s help with fieldwork was greatly appreciated. This study was made possible by a NERC PhD studentship and financial support from the Royal Botanic Garden Edinburgh and Scottish Natural Heritage.Peer reviewedPostprin

Natriuretic peptide vs. clinical information for diagnosis of left ventricular systolic dysfunction in primary care

<p>Abstract</p> <p>Background</p> <p>Screening of primary care patients at risk for left ventricular systolic dysfunction by a simple blood-test might reduce referral rates for echocardiography. Whether or not natriuretic peptide testing is a useful and cost-effective diagnostic instrument in primary care settings, however, is still a matter of debate.</p> <p>Methods</p> <p>N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, clinical information, and echocardiographic data of left ventricular systolic function were collected in 542 family practice patients with at least one cardiovascular risk factor. We determined the diagnostic power of the NT-proBNP assessment in ruling out left ventricular systolic dysfunction and compared it to a risk score derived from a logistic regression model of easily acquired clinical information.</p> <p>Results</p> <p>23 of 542 patients showed left ventricular systolic dysfunction. Both NT-proBNP and the clinical risk score consisting of dyspnea at exertion and ankle swelling, coronary artery disease and diuretic treatment showed excellent diagnostic power for ruling out left ventricular systolic dysfunction. AUC of NT-proBNP was 0.83 (95% CI, 0.75 to 0.92) with a sensitivity of 0.91 (95% CI, 0.71 to 0.98) and a specificity of 0.46 (95% CI, 0.41 to 0.50). AUC of the clinical risk score was 0.85 (95% CI, 0.79 to 0.91) with a sensitivity of 0.91 (95% CI, 0.71 to 0.98) and a specificity of 0.64 (95% CI, 0.59 to 0.67). 148 misclassifications using NT-proBNP and 55 using the clinical risk score revealed a significant difference (McNemar test; p < 0.001) that was based on the higher specificity of the clinical risk score.</p> <p>Conclusion</p> <p>The evaluation of clinical information is at least as effective as NT-proBNP testing in ruling out left ventricular systolic dysfunction in family practice patients at risk. If these results are confirmed in larger cohorts and in different samples, family physicians should be encouraged to rely on the diagnostic power of the clinical information from their patients.</p

Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality in preterm infants. NEC is characterized by an exaggerated inflammatory response to bacterial flora leading to bowel necrosis. Bacterial lipopolysaccharide (LPS) mediates inflammation through TLR4 activation and is a key molecule in the pathogenesis of NEC. However, LPS also induces cyclooxygenase-2 (COX-2), which promotes intestinal barrier restitution through stimulation of intestinal cell survival, proliferation, and migration. Epidermal growth factor receptor (EGFR) activation prevents experimental NEC and may play a critical role in LPS-stimulated COX-2 production. We hypothesized that EGFR is required for LPS induction of COX-2 expression. Our data show that inhibiting EGFR kinase activity blocks LPS-induced COX-2 expression in small intestinal epithelial cells. LPS induction of COX-2 requires Src-family kinase signaling while LPS transactivation of EGFR requires matrix metalloprotease (MMP) activity. EGFR tyrosine kinase inhibitors block LPS stimulation of mitogen-activated protein kinase ERK, suggesting an important role of the MAPK/ERK pathway in EGFR-mediated COX-2 expression. LPS stimulates proliferation of IEC-6 cells, but this stimulation is inhibited with either the EGFR kinase inhibitor AG1478, or the selective COX-2 inhibitor Celecoxib. Taken together, these data show that EGFR plays an important role in LPS-induction of COX-2 expression in enterocytes, which may be one mechanism for EGF in inhibition of NEC

Patients’ and clinicians’ views on the optimum schedules for self-monitoring of blood pressure

This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by the Royal College of General Practitioners.Background Self-monitoring of blood pressure is common but guidance on how it should be carried out varies and it is currently unclear how such guidance is viewed. Aim To explore patients' and health care professionals' (HCPs) views and experiences of the use of different self-monitoring regimes, to determine what is acceptable and feasible and to inform future recommendations. Design and Setting Thirteen focus groups plus four HCP interviews were held, total of 66 participants (41 patients, 25 HCPs) from primary and secondary care with and without experience of self-monitoring. Method Both standard and shortened self-monitoring protocols were considered. Focus groups and interviews were recorded, transcribed verbatim and analysed by constant comparative method. Results Patients generally supported structured schedules but with sufficient flexibility to allow adaptation to individual routine. They preferred a shorter (3-day) schedule to longer (7-day) regimes. Whilst HCPs could describe benefits for patients of using a schedule, they were reluctant to recommend a specific schedule. Concerns surrounded the use of different schedules for diagnosis and subsequent monitoring. Appropriate education was seen as vital by all participants to enable a self-monitoring schedule to be followed at home. Conclusions There is not a 'one size fits all approach' to developing the optimum protocol from the perspective of users and those implementing it. An approach whereby patients are asked to complete the minimum number of readings required for accurate BP estimation in a flexible manner seems most likely to succeed. Informative advice and guidance should incorporate such flexibility for patients and professionals alike.This study was independent research commissioned by the National Institute for Health Research (NIHR) as part of a Programme Grant for Applied Research “Optimising the diagnosis and management of hypertension in primary care through self-monitoring of blood pressure” (RP-PG-1209-10051). RJM receives funding from an NIHR Professorship (NIHR-RP-02-12-015). FDRH is part funded by the National Institute for Health Research (NIHR) School for Primary Care Research (SPCR), NIHR Oxford Biomedical Research Centre (BRC), NIHR Oxford Collaboration for Leadership in Applied Health Research (CLAHRC), and is supported by Harris Manchester College, Oxford. Sheila Greenfield is supported by the NIHR CLAHRC West Midlands initiative

The Pheromone of the Cave Cricket, Hadenoecus cumberlandicus, Causes Cricket Aggregation but Does Not Attract the Co-Distributed Predatory Spider, Meta ovalis

Food input by the cave cricket, Hadenoecus cumberlandicus Hubble & Norton (Orthoptera: Rhaphidophoridae), is vital to the cave community, making this cricket a true keystone species. Bioassays conducted on cave walls and in the laboratory show that clustering in H. cumberlandicus is guided by a pheromone, presumably excreta. This aggregation pheromone was demonstrated by using filter paper discs that had previous adult H. cumberlandicus exposure, resulting in > 70% response by either nymphs or adults, prompting attraction (thus, active component is a volatile), followed by reduced mobility (arrestment) on treated surfaces. Adults were similarly responsive to pheromone from nymphs, agreeing with mixed stage composition of clusters in the cave. Effects of [0.001M – 0.1M] uric acid (insect excreta's principle component) on H. cumberlandicus behavior were inconsistent. This pheromone is not a host cue (kairomone) and is not used as a repellent (allomone) as noted through lack of responses to natural H. cumberlandicus pheromone and uric acid concentrations by a co-occurring predatory cave orb weaver spider, Meta ovalis Gertsch (Araneae: Tetragnathidae). This pheromone is not serving as a sex pheromone because nymphs were affected by it and because this population of H. cumberlandicus is parthenogenic. The conclusion of this study is that the biological value of the aggregation pheromone is to concentrate H. cumberlandicus in sheltered sites in the cave conducive for minimizing water stress. Rather than signaling H. cumberlandicus presence and quality, the reduced mobility expressed as a result of contacting this pheromone conceivably may act as a defense tactic (antipredator behavior) against M. ovalis, which shares this favored habitat site

The use of otolith strontium isotopes (87Sr/86Sr) to identify nursery habitat for a threatened estuarine fish

Nursery habitats are larval or juvenile habitats that disproportionately contribute individuals to adult populations of a species. Identifying and protecting such habitats is important to species conservation, yet evaluating the relative contributions of different larval habitats to adult fish populations has proven difficult at best. Otolith geochemistry is one available tool for reconstructing previous habitat use of adult fishes during the early life history, thus facilitating the identification of nursery habitats. In this study, we compared traditional catch surveys of larval-stage longfin smelt (Spirinchus thaleichthys) occurring in habitats of different salinities to corresponding larval-stage salinity distributions of sub-adult/adult longfin smelt estimated using otolith geochemical techniques. This allowed us to evaluate the relative contribution of larvae from waters of various salinities to sub-adult/adult populations of longfin smelt. We used laser ablation MC-ICP-MS on otoliths and an empirically-derived relationship between strontium isotope ratios (87Sr/86Sr) of waters across the estuarine salinity gradient to reconstruct the larval salinity history of longfin smelt. Salinity values from the larval region of sub-adult/adult otoliths (corresponding to standard lengths of ca.10-mm) were compared to corresponding catch distribution of larval longfin smelt (≤ 10-mm) from 4 year-classes (1999, 2000, 2003 and 2006) in the San Francisco Estuary spanning a period when the population underwent a dramatic decline. Though the catch distribution of larval-stage longfin smelt was centered around 4-ppt and did not vary significantly among years, salinity distributions of sub-adult/adult were lower and narrower (ca. 2-ppt), suggesting that low-salinity habitats disproportionally contributed more recruits relative to both freshwater and brackish water habitats and, therefore, may function as important nursery areas. Furthermore, the relative importance of the low salinity zone (ca. 2-ppt) to successful recruitment appeared greatest in years following the longfin smelt population decline. Our results indicate that otolith strontium isotopes (87Sr/86Sr) are a powerful tool for identifying nursery habitats for estuarine fishes

Naturally occurring hybrids of coral reef butterflyfishes have similar fitness compared to parental species.

Hybridisation can produce evolutionary novelty by increasing fitness and adaptive capacity. Heterosis, or hybrid vigour, has been documented in many plant and animal taxa, and is a notable consequence of hybridisation that has been exploited for decades in agriculture and aquaculture. On the contrary, loss of fitness in naturally occurring hybrid taxa has been observed in many cases. This can have negative consequences for the parental species involved (wasted reproductive effort), and has raised concerns for species conservation. This study evaluates the relative fitness of previously documented butterflyfish hybrids of the genus Chaetodon from the Indo-Pacific suture zone at Christmas Island. Histological examination confirmed the reproductive viability of Chaetodon hybrids. Examination of liver lipid content showed that hybrid body condition was not significantly different from parent species body condition. Lastly, size at age data revealed no difference in growth rates and asymptotic length between hybrids and parent species. Based on the traits measured in this study, naturally occurring hybrids of Chaetodon butterflyfishes have similar fitness to their parental species, and are unlikely to supplant parental species under current environmental conditions at the suture zone. However, given sufficient fitness and ongoing genetic exchange between the respective parental species, hybrids are likely to persist within the suture zone

Strongly magnetized pulsars: explosive events and evolution

Well before the radio discovery of pulsars offered the first observational confirmation for their existence (Hewish et al., 1968), it had been suggested that neutron stars might be endowed with very strong magnetic fields of $10^{10}$-$10^{14}$G (Hoyle et al., 1964; Pacini, 1967). It is because of their magnetic fields that these otherwise small ed inert, cooling dead stars emit radio pulses and shine in various part of the electromagnetic spectrum. But the presence of a strong magnetic field has more subtle and sometimes dramatic consequences: In the last decades of observations indeed, evidence mounted that it is likely the magnetic field that makes of an isolated neutron star what it is among the different observational manifestations in which they come. The contribution of the magnetic field to the energy budget of the neutron star can be comparable or even exceed the available kinetic energy. The most magnetised neutron stars in particular, the magnetars, exhibit an amazing assortment of explosive events, underlining the importance of their magnetic field in their lives. In this chapter we review the recent observational and theoretical achievements, which not only confirmed the importance of the magnetic field in the evolution of neutron stars, but also provide a promising unification scheme for the different observational manifestations in which they appear. We focus on the role of their magnetic field as an energy source behind their persistent emission, but also its critical role in explosive events.Comment: Review commissioned for publication in the White Book of "NewCompStar" European COST Action MP1304, 43 pages, 8 figure

Perceived barriers for treatment of chronic heart failure in general practice; are they affecting performance?

BACKGROUND: The aim of this study is to determine to what extent barriers perceived by general practitioners (GPs) for prescribing angiotensin-converting enzyme inhibitors (ACE-I) in chronic heart failure (CHF) patients are related to underuse and underdosing of these drugs in actual practice. METHODS: Barriers were assessed with a semi-structured questionnaire. Prescribing data were extracted from GPs' computerised medical records for a random sample of their CHF patients. Relations between barriers and prescribing behaviour were assessed by means of Spearman rank correlation and multivariate regression modelling. RESULTS: GPs prescribed ACE-I to 45% of their patients and had previously initiated such treatment in an additional 3.5%, in an average standardised dose of 13.5 mg. They perceived a median of four barriers in prescribing ACE-I or optimising ACE-I dose. Many GPs found it difficult to change treatment initiated by a cardiologist. Furthermore, initiating ACE-I in patients already using a diuretic or stable on their current medication was perceived as barrier. Titrating the ACE-I dose was seen as difficult by more than half of the GPs. No significant relationships could be found between the barriers perceived and actual ACE-I prescribing. Regarding ACE-I dosing, the few GPs who did not agree that the ACE-I should be as high as possible prescribed higher ACE-I doses. CONCLUSION: Variation between GPs in prescribing ACE-I for CHF cannot be explained by differences in the barriers they perceive. Tailor-made interventions targeting only those doctors that perceive a specific barrier will therefore not be an efficient approach to improve quality of care