MBE growth, characterisation and physics of antiferromagnetic copper manganese arsenide

Research into antiferromagnetic materials for application in spintronics has rapidly expanded in recent years. The prediction and observation of spin based phenomena with antiferromagnets as the active components, has expanded the field and there is a need for high quality materials that are compatible with existing III-V semiconductor systems to expand this research. Copper manganese arsenide is one such material and will be the subject of this thesis. Early studies had shown that this material grows epitaxially on both gallium arsenide and gallium phosphide substrates by molecular beam epitaxy. This thesis builds on this early work by further characterising CuMnAs, improving the techniques used to grow it, and enhancing our understanding of the material. A key result of this thesis is that the Néel temperature of CuMnAs can be studied using temperature dependent transport measurements. This method allows for a range of layer thickness (from between 5 and 140 nm) to be studied. We find that the Néel temperature of CuMnAs is suppressed by around 100K when the layer thickness is less than 10nm. At the thicknesses studied there is agreement (around (480±5)K) with the more established neutron diffraction technique for measuring Néel temperature, which was also used to determine the magnetic structure of the CuMnAs studied. In addition to measurement of the Néel temperature of CuMnAs, a detailed study is made in this thesis of the ideal growth conditions for ultrathin (sub 10nm) films of CuMnAs. Post-growth examination of ultrathin layers of CuMnAs showed that significant portions of material were missing due to poor adhesion. This thesis shows the results of the development of several different nucleation and growth methods, which were used to improve the adhesion of the CuMnAs layer to the substrate. These methods are evaluated using atomic force microscopy, x-ray diffraction, magnetometry and transport measurements. CuMnAs has previously shown to strongly prefer growth under stoichiometric conditions, as non-stoichiometric conditions have tended to favour the formation of clusters of the excess material. In excess Mn conditions these clusters are ferromagnetic MnAs inclusions that are conducting and contribute to the magnetic behaviour. This thesis presents the results of a simulation study of the conductivity of ferromagnetic elements in a non-ferromagnetic medium. This approach could be extended to allow the number of inclusions in a CuMnAsl layer to be approximated from transport measurements. Finally, this thesis will also look at the effects of alloying CuMnAs with phosphorous. This reduces the lattice constants of the material while retaining the same crystal and magnetic structure. In thick films of the alloy the Néel temperature increases from that of CuMnAs

MBE growth, characterisation and physics of antiferromagnetic copper manganese arsenide

Research into antiferromagnetic materials for application in spintronics has rapidly expanded in recent years. The prediction and observation of spin based phenomena with antiferromagnets as the active components, has expanded the field and there is a need for high quality materials that are compatible with existing III-V semiconductor systems to expand this research. Copper manganese arsenide is one such material and will be the subject of this thesis. Early studies had shown that this material grows epitaxially on both gallium arsenide and gallium phosphide substrates by molecular beam epitaxy. This thesis builds on this early work by further characterising CuMnAs, improving the techniques used to grow it, and enhancing our understanding of the material. A key result of this thesis is that the Néel temperature of CuMnAs can be studied using temperature dependent transport measurements. This method allows for a range of layer thickness (from between 5 and 140 nm) to be studied. We find that the Néel temperature of CuMnAs is suppressed by around 100K when the layer thickness is less than 10nm. At the thicknesses studied there is agreement (around (480±5)K) with the more established neutron diffraction technique for measuring Néel temperature, which was also used to determine the magnetic structure of the CuMnAs studied. In addition to measurement of the Néel temperature of CuMnAs, a detailed study is made in this thesis of the ideal growth conditions for ultrathin (sub 10nm) films of CuMnAs. Post-growth examination of ultrathin layers of CuMnAs showed that significant portions of material were missing due to poor adhesion. This thesis shows the results of the development of several different nucleation and growth methods, which were used to improve the adhesion of the CuMnAs layer to the substrate. These methods are evaluated using atomic force microscopy, x-ray diffraction, magnetometry and transport measurements. CuMnAs has previously shown to strongly prefer growth under stoichiometric conditions, as non-stoichiometric conditions have tended to favour the formation of clusters of the excess material. In excess Mn conditions these clusters are ferromagnetic MnAs inclusions that are conducting and contribute to the magnetic behaviour. This thesis presents the results of a simulation study of the conductivity of ferromagnetic elements in a non-ferromagnetic medium. This approach could be extended to allow the number of inclusions in a CuMnAsl layer to be approximated from transport measurements. Finally, this thesis will also look at the effects of alloying CuMnAs with phosphorous. This reduces the lattice constants of the material while retaining the same crystal and magnetic structure. In thick films of the alloy the Néel temperature increases from that of CuMnAs

Imaging current-induced switching of antiferromagnetic domains in CuMnAs

The magnetic order in antiferromagnetic materials is hard to control with external magnetic fields. Using X-ray Magnetic Linear Dichroism microscopy, we show that staggered effective fields generated by electrical current can induce modification of the antiferromagnetic domain structure in microdevices fabricated from a tetragonal CuMnAs thin film. A clear correlation between the average domain orientation and the anisotropy of the electrical resistance is demonstrated, with both showing reproducible switching in response to orthogonally applied current pulses. However, the behavior is inhomogeneous at the submicron level, highlighting the complex nature of the switching process in multi-domain antiferromagnetic films

Factors Predicting Long-term Outcome and the Need for Surgery in Graves Orbitopathy: Extended Follow-up From the CIRTED Trial

UNLABELLED: Graves Orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of follow-up. METHODS: 3 year follow-up of a subset of the CIRTED trial (N=68) which randomized patients to receive high dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy. RESULTS: Data were available at 3 years from 68 of 126 randomised subjects (54%). No additional benefit was seen at 3 years for patients randomized to azathioprine or radiotherapy with regard to a Binary Clinical Composite Outcome Measure, modified EUGOGO score or Ophthalmopathy Index.Clinical Activity Score (CAS), Ophthalmopathy Index and Total Eye Score improved over 3 years (p<0.001). However, quality of life at 3 years remained poor. Of 64 individuals with available surgical outcome data, 24/64 (37.5%) required surgical intervention. Disease duration of greater than 6 months before treatment was associated with increased need for surgery OR=16.8 (95%CI 2.95, 95.0) p=0.001. Higher baseline levels of CAS, Ophthalmopathy Index and Total Eye Score but not early improvement in CAS were associated with increased requirement for surgery. CONCLUSION: In this long-term follow-up from a clinical trial, 3 year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes

Antiferromagnetic structure in tetragonal CuMnAs thin films

Tetragonal CuMnAs is an antiferromagnetic material with favourable properties for applications in spintronics. Using a combination of neutron diffraction and x-ray magnetic linear dichroism, we determine the spin axis and magnetic structure in tetragonal CuMnAs, and reveal the presence of an interfacial uniaxial magnetic anisotropy. From the temperature-dependence of the neutron diffraction intensities, the Néel temperature is shown to be (480 ± 5) K. Ab initio calculations indicate a weak anisotropy in the (ab) plane for bulk crystals, with a large anisotropy energy barrier between in-plane and perpendicular-to-plane directions

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

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

Factors Predicting Long-term Outcome and the Need for Surgery in Graves Orbitopathy:Extended Follow-up From the CIRTED Trial

Graves orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of follow-up. Methods Three-year follow-up of a subset of the CIRTED trial (N = 68), which randomized patients to receive high-dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy. Results Data were available at 3 years from 68 of 126 randomized subjects (54%). No additional benefit was seen at 3 years for patients randomized to azathioprine or radiotherapy with regard to a binary clinical composite outcome measure (BCCOM), modified European Group on Graves’ Orbitopathy score, or Ophthalmopathy Index. Clinical Activity Score (CAS), Ophthalmopathy Index, and Total Eye Score improved over 3 years (P < .001). However, quality of life at 3 years remained poor. Of 64 individuals with available surgical outcome data, 24 of 64 (37.5%) required surgical intervention. Disease duration of greater than 6 months before treatment was associated with increased need for surgery [odds ratio (OR) 16.8; 95% CI 2.95, 95.0; P = .001]. Higher baseline levels of CAS, Ophthalmopathy Index, and Total Eye Score but not early improvement in CAS were associated with increased requirement for surgery. Conclusion In this long-term follow-up from a clinical trial, 3-year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes